Pharmaceutical dosage form

ABSTRACT

The invention relates to a pharmaceutical dosage form, preferably with controlled release of a pharmacologically active compound (A) contained therein, the pharmaceutical dosage form very preferably being tamper-resistant and most preferably having a breaking strength B 1  of at least 500 N in direction of extension E 1  and having a breaking strength B 2  of less than 500 N in direction of extension E 2 .

This application is a division of U.S. patent application Ser. No.12/358,415 filed Jan. 23, 2009, now allowed, which claims foreignpriority of European Patent Application No. 08018221.5 filed Oct. 17,2008; European Patent Application No. 08001416.0 filed Jan. 25, 2008;and European Patent Application No. 08001415.2 filed Jan. 25, 2008, thedisclosures of which are incorporated herein by reference.

FIELD OF THE INVENTION

The invention relates to a pharmaceutical dosage form, preferably atablet for oral administration.

BACKGROUND ART

For many pharmaceutically active compounds it is still preferred to havethem orally administered by way of tablets. It is also well known thatdepending on how a pharmaceutically active ingredient is formulated intoa tablet its release pattern can be modified. In this regard, tabletsproviding a retarded release profile are of primary importance. Withretarded release tablets care has to be taken that under nocircumstances the pharmaceutically active ingredient will be releasedcompletely and instantaneously in an uncontrolled manner(“dose-dumping”) since regularly the dosage used for retarded releasetablets is much higher than for non-retarded release tablets. This maycause serious adverse effects or even death depending on the activeingredient and potency thereof.

Controlled release (e.g. delayed release, prolonged release, sustainedrelease, and the like) may be based upon various concepts such ascoating the pharmaceutical dosage form with a controlled releasemembrane, embedding the pharmacologically active compound in a matrix,binding the pharmacologically active compound to an ion-exchange resin,forming a complex of the pharmacologically active compound, and thelike. In this context it can be referred to, e.g., W. A. Ritschel, DieTablette, 2. Auflage, Editio Cantor Verlag Aulendorf, 2002.

In WO 01/97783 A1 a controlled-release, in particular a retarded releaseoral drug dosage form for releasing a drug into at least a portion of aregion defined by the stomach and the front gastrointestinal tract isobtained by employing a solid monolithic matrix having a non-circularshape wherein the longitudinal axis has a maximum length of 3.0 cm andthe transversal axis achieves a minimum length of 1.2 cm within one hourof immersion in water. Furthermore, it is required that the matrix has ashape which when projected onto a plane is either an oval or aparallelogram.

U.S. Pat. No. 4,353,887 discloses a divisible tablet which exhibitscontrolled and delayed release of an active substance. This is achievedby use of a coating on a compacted tablet having an oblong shape inwhich the ratio of length to width to depth is approximately 2.5 to 5:approximately 0.9 to 2:1 and the width constitute at most ⅔ of thelength. In addition, one or more relatively deep dividing grooves haveto be present which run perpendicular to the length and depth and have atotal depth of from approximately ⅓ to approximately ½ of the depth ofthe tablet.

WO 01/08661 is directed to a controlled release formulation, capable ofproviding sustained, prolonged, repeat and/or delayed release ofoxycodone.

WO 03/094812 relates to abuse-resistant opioid-containing solid dosagepharmaceuticals comprising a sustained release carrier and ananalgesically effective amount of an opioid analgesic in combinationwith an opioid euphoria-inhibiting amount of an isolated nontoxicN-methyl-D-aspartate receptor antagonist which is substantially notreleased when the dosage form is administered intact.

WO 99/48481 discloses a tablet for the controlled release of an activepharmaceutical ingredient. The tablet comprises a core having adonut-like configuration with a cylindrical hole extending through thecenter of the core. The core is coated with a hydrophobic,water-insoluble material covering all of the core except that which isdefined by the cylindrical hole.

GB-A 2 057 878 discloses a divisible tablet having controlled anddelayed release of the active substance, consisting of a compact that isformed by at least one active substance in an adjunct composition thateffects a delayed and controlled release of the active substance, thecompact being of an oblong shape in which the ratio of length to widthto depth is approximately 2.5 to 5: approximately 0.9 to 2:1 and thewidth constitutes at most ⅔ of the length, and in which one or morerelatively deep dividing grooves are present which run perpendicularlyto the length and depth and have a total depth of from approximately 113to approximately '12 of the depth of the tablet, but are at least sodeep that one fracture surface area multiplied by the number of possiblefragments constitutes a maximum of 15% of the surface area of theundivided tablet, the base and top faces independently of one anotherare planar or are convexly curved about the longitudinal axis or aboutparallels to this axis, the side faces are planar, the end faces can beof any shape and edges are optionally bevelled or rounded.

DE-A 198 56 147 discloses a solid, elongate dosage form with a long axisand with a length which is defined by projection of the ends of thedosage form onto the long axis, where a cross-sectional area orientedperpendicular to the long axis has an area which is variable along thelong axis and increases from a cross-sectional area which is locatedbetween the ends and has a minimal area essentially continuously towardthe two ends up to in each case a cross-sectional area with a maximalarea, wherein the distance of the maximal cross-sectional area which islocated near one end from the maximal cross-sectional area which islocated near the other end is, projected on the long axis, more thanhalf the length of the dosage form.

DE 28 08 505 C2 discloses a tablet which dissolves at essentiallyconstant speed and which contains a water soluble component as well as awater insoluble coating. It is required that the side of the tablet hasto comprise one or more cavities having a breadth of 0.1 to 1.0 mm, adepth of 0.1 to 0.4 mm and a length of more than 0.1 mm, wherein theside of said cavities is less than ⅙ of the total side of the tablet.

In DE 692 29 881 T2 it is proposed to obtain a tablet having a retardedrelease profile by use of a water soluble gel as well as of a specificcoating having a specific thickness. The coating has to contain eitherethylcellulose or acetylcellulose and has to be water insoluble as wellas insoluble in gastric liquids.

A tablet having a controlled release profile will according to WO99/48481A1 be obtained by use of a doughnut-shaped core material with acylindrical hole. A hydrophobic, water-insoluble coating is applied tothe doughnut-shaped core except for the side of said core whichsurrounds the cylindrical hole. In such a manner an inherent limitationof compressed monolithic tablets for extended release dosages shall beovercome, namely the increase in diffusion length resistance over timedue to the insolubility of the polymer. Apparently, this problem hasbeen solved by insuring that the inner exposed area of thedoughnut-shaped configuration is clear of any coating.

In DE 42 39 085 A1 it is described to make use of an oblong tablet onlythe opposed edges of which are in contact with an underlying side butnot the intermediate section. In this manner the tablet is easilydivisible by use of one hand only. The two parts forming such an oblongtablet may have the form of spherical sectors.

It is well known that a pharmaceutical formulation or its mode ofmanufacture, e.g. for an oral dosage form, might undergo modificationsduring clinical testing, for example with respect to the ingredientsused or to the relative amounts of the excipients, or with respect tothe reaction conditions and reactants used during manufacture.Frequently, such modifications at least to some extent have an impact onthe release profile of pharmaceutically active ingredients. This isparticularly unpleasant if for a specific formulation an approvedoptimized release profile has already been found which can not bereproduced with the modified formulation. In such a case, the clinicaltests have either to be interrupted or have to be started from thebeginning. Given the huge expenditures necessary to bring a new drugformulation up to and through clinical testing the above scenario hasindeed proven to be rather unsatisfactory.

Pharmaceutical dosage forms having an increased breaking strength(resistance to crushing) have been recently reported. Dosage forms ofthis type may also exhibit a certain degree of controlled release of thepharmacologically active compound contained therein. The major advantageof such pharmaceutical dosage forms is that comminuting, particularlypulverization, by conventional means, such as grinding in a mortar orfracturing by means of a hammer, is impossible or at least substantiallyimpeded.

On the one hand, pharmaceutical dosage forms having an increasedbreaking strength are useful for avoiding drug abuse of thepharmacologically active compound contained therein. Many pharmaceuticalactive compounds, in addition to having excellent activity in theirappropriate application, also have abuse potential, i.e., they can beused by an abuser to bring about effects other than those intended.Opiates, for example, which are highly active in combating severe tovery severe pain, are frequently used by abusers to induce a state ofnarcosis or euphoria. In order to make abuse possible, the correspondingpharmaceutical dosage forms, such as tablets or capsules are comminuted,for example ground in a mortar, by the abuser, the active compound isextracted from the resultant powder using a preferably aqueous liquidand the resultant solution, optionally after being filtered throughcotton wool or cellulose wadding, and is administered parenterally, inparticular intravenously. An additional phenomenon of this kind ofadministration, in comparison with abusive oral administration, is afurther accelerated increase in active compound levels giving the abuserthe desired effect, namely the “kick” or “rush”. This kick is alsoobtained if the powdered pharmaceutical dosage form is administerednasally, i.e. is sniffed. Since controlled-release pharmaceutical dosageforms containing active compounds with abuse potential do not give riseto the kick desired by the abuser when taken orally even in abusivelyhigh quantities, such pharmaceutical dosage forms are also comminutedand extracted in order to be abused. Pharmaceutical dosage formsexhibiting an increased breaking strength, however, may not be powderedby conventional means and thus, cannot be administered nasally therebyavoiding drug abuse. In the context of such tamper resistant dosageforms, it can be referred to, e.g., WO 2005/016313, WO 2005/016314, WO2005/063214, WO 2005/102286, WO 2006/002883, WO 2006/002884, WO2006/002886, and WO 2006/082097.

These dosage forms have a breaking strength of at least 500 N in everydirection of extension.

On the other hand, pharmaceutical dosage forms having an increasedbreaking strength are useful for avoiding an (unintentional) overdose ofthe pharmacologically active compound contained therein, which overdosewould otherwise be caused by diminishing the retardant effect due topulverization. It is known that many patients, particularly olderpatients frequently have difficulties in taking solid pharmaceuticaldosage forms, such as tablets, gelatine capsules, etc. They choke onthem and sometimes develop pronounced aversion to such pharmaceuticaldosage forms. To counter this problem, various apparatuses have beendeveloped by means of which conventional solid pharmaceutical dosageforms may be comminuted or pulverized (“tablet crushers”). Suchapparatuses are used, for example, by the care staff in old people'shomes. The pharmaceutical dosage forms are then administered to thepeople being cared for not as tablets etc. but rather as powder, forexample to get round the difficulties involved in swallowing tablets.However, the comminution of pharmaceutical dosage forms with suchapparatuses is problematic if the pharmaceutical dosage forms areprolonged-release formulations. As a rule, comminution results indestruction of the inner structure of the pharmaceutical dosage form,which is responsible for the prolonged release, so doing away with theprolonged-release action. Consequently, after administration, frequentlyall the physiologically active substance originally contained in thepharmaceutical dosage form is released in a relatively short time,whereby a comparatively very high plasma concentration of the substanceis abruptly reached within a relatively short time frame. In this way,the originally prolonged-release formulations become immediate releaseformulations. Depending on the physiological activity of the substance,this may cause considerable side-effects however, and in extreme casesmay even lead to the death of the patient. Pharmaceutical dosage formshaving an increased breaking strength, however, cannot be comminuted bytablet crushers and thus, have to be swallowed as a whole therebyavoiding any (unintentional) overdose. In this context, it can befurther referred to, e.g., WO 2006/082099.

These dosage forms also have a breaking strength of at least 500 N inevery direction of extension.

The release profile of controlled-release formulations depends on avariety of factors, such as properties of the pharmaceutical dosage formper se, nature and content of the matrix, nature of the release medium,nature and content of the active compound, nature and content of furtherpharmaceutical excipients as well as the interrelationship of thesefactors. When the control of the release profile relies on a polymermatrix in which the active compound is embedded, the release ratedepends on the properties of the pharmaceutical dosage form as such,e.g. its geometry, method of manufacture, additives and excipientscontained therein, and the like. Further, the release rate depends onthe properties of the matrix polymer, such as molecular weight,viscosity, particle properties, interaction with other polymers, chainentanglements, degree of cross-linking, chemical nature of monomerunits, interaction of the matrix material with the release medium (e.g.,swelling and gelling), and the like. Still further, the release ratedepends on the properties of the active compound, e.g., its dose,particle size, particle form and its solubility in the release medium,which in turn is a function of various properties, such as molecularsize, molecular weight, ionogenicity, acidity, steric hindrance,arrangement of dipols, hydrophilicity, etc. Furthermore, the releaserate depends on the individual interactions of a given matrix materialwith a given active compound (cf. Ning Wu et al., Journal of ControlledRelease 102 (2005) 569-81; V. S. Manthena et al., Am J Drug Deliv. 20042(1) 43-57).

The release profile of conventional pharmaceutical dosage forms that donot exhibit an increased breaking strength can usually be adjustedwithin certain limits, usually by the variation of the content and/orthe nature of the pharmaceutical excipients, such as the matrix formingpolymer.

In some cases it has also been reported that the release of a drug inthe body can be controlled by the surface area to volume ratio of aconventional dosage form which does not exhibit an increased breakingstrength. For example, U.S. Pat. No. 5,427,798 discloses film coatedtablets containing bupropion hydrochloride and having a surface area totablet volume of 3:1 to 25:1 cm⁻¹ for tablets of 50, 100 and 150 mg drugcontent. Similarly, U.S. Pat. No. 4,940,556 and U.S. Pat. No. 5,198,226disclose spheroids containing dihydropyridine calcium channel blockersand having area radius to circumference radius ratios in the range of0.85 to 1.0.

With respect of pharmaceutical dosage forms exhibiting an increasedbreaking strength, however, the variation of the content, the nature ofthe pharmaceutical excipients and/or the surface area to volume ratioalso affects the mechanical properties. This is because the increasedbreaking strength of the pharmaceutical dosage form typically relies onthe presence of a particular polymer that is processed by a particularmethod when manufacturing the pharmaceutical dosage form. It seems thatsaid polymer also serves as a matrix embedding the pharmacologicallyactive compound. In consequence, the polymer matrix that is essential tothe breaking strength of the pharmaceutical dosage form simultaneouslyserves as a controlled release matrix and thus, varying the content,nature and/or spacial distribution of the polymer causes both, a changeof the release profile as well as a change of the mechanical propertiesof the pharmaceutical dosage form.

Particular problems arise when the dose of the pharmacologically activecompound and thus, also the total weight of the pharmaceutical dosageform is comparatively high. Depending upon the content and the nature ofthe pharmacologically active compound and of the pharmaceuticalexcipients, the retardant effect of the polymer may be so strong thatthe pharmaceutical dosage form cannot be adapted to a specific dosingregimen, e.g., twice daily, particularly when the increased breakingstrength is to be maintained.

On the one hand, a decrease of the content of the retardant polymer forthe purpose of accelerating drug release would substantially affect themechanical properties of the pharmaceutical dosage form and in a worstcase scenario, would completely diminish its specific and uniquemechanical properties (breaking strength). Further, a decrease of thecontent of the matrix polymer beyond a certain limit may cause adeterioration or even loss of other desired properties, such as storagestability. A poor storage stability results, e.g., in a change of therelease profile over time.

On the other hand, the addition of non-retardant pharmaceuticalexcipients (auxiliaries) for the purpose of weakening the retardanteffect of the retardant polymer would increase the total weight of thedosage form. As highly dosed pharmaceutical dosage forms havecomparatively high total weights anyway, a further increase of the totalweight is disadvantageous and could deteriorate patient compliance (e.g.swallowability).

Thus, there is a demand for pharmaceutical dosage forms, particularlytamper-resistant pharmaceutical dosage forms, the release profile ofwhich may be varied within certain limits without diminishing the tamperresistance and without deteriorating the compliance of thepharmaceutical dosage form.

It, thus, has been an object of the present invention to provide an oraldosage form which does not exhibit the shortcomings of the dosage formsof the state of the art and which in particular allows for an improvedcontrol of the release profile of the active pharmaceutical ingredientincorporated in the oral dosage form. It has been another object of thepresent invention to be able to regain the original release profile ofan elaborated formulation for an oral dosage form, the release patternof which has experienced changes due to modifications to the compositionof said formulation.

This object has been solved by the subject-matter described hereinbelow.

SUMMARY OF THE INVENTION

The present invention relates in a first aspect to a pharmaceuticaldosage form, especially an oral dosage form, particularly a tablet,comprising at least one pharmaceutically active ingredient, and having ashape comprising a longitudinal axis and two opposite longitudinaledges, a transversal axis perpendicular to the longitudinal axis and twoopposite transversal edges, a front side, an opposite back side and acircumferential rim between said front and back side, wherein the frontside and/or the back side comprise a basis area and wherein the frontside and/or the back side comprise at least one bulge which extendsabove said basis area, said at least one bulge being present at and/oradjacent to at least a section of one or both longitudinal edges and/orat and/or adjacent to at least a section of one or both transversaledges and/or between both longitudinal edges and both transversal edges.The front side and/or the back side of the dosage form, in particularthe basis area of the front side and/or the basis area of the back side,can further comprise at least one indentation.

The present invention relates in a second aspect to a tamper-resistantpharmaceutical dosage form having a retarded release profile, especiallya tamper-resistant oral dosage form having a retarded release profile,particularly a tamper-resistant tablet having a retarded releaseprofile, comprising at least one pharmaceutically active ingredient withpotential for abuse, and having a shape comprising a longitudinal axisand two opposite longitudinal edges, a transversal axis perpendicular tothe longitudinal axis and two opposite transversal edges, a front side,an opposite back side and a circumferential rim between said front andback side, wherein the front side and/or the back side comprise a basisarea and wherein the front side and/or the back side comprise at leastone bulge which extends above said basis area, said at least one bulgebeing present at and/or adjacent to at least a section of one or bothlongitudinal edges and/or at and/or adjacent to at least a section ofone or both transversal edges and/or between both longitudinal edges andboth transversal edges. The front side and/or the back side of thedosage form, in particular the basis area of the front side and/or thebasis area of the back side, can further comprise at least oneindentation.

The present invention relates in a third aspect to a pharmaceuticaldosage form with controlled release of a pharmacologically activecompound (A) contained therein, the pharmaceutical dosage form having abreaking strength B₁ of at least 500 N in direction of extension E₁ andhaving a breaking strength B₂ of less than 500 N in direction ofextension E₂.

The pharmaceutical dosage forms according to the invention preferablyexhibit anisotropic mechanical properties (i.e., different mechanicalproperties in different directions).

With the dosage form of the invention, preferably a tablet, it ispossible to have in general a greater control on the release profile ofpharmaceutically active ingredients. The release profile can be finelyadjusted or tailored in a more accurate, predictable and reliablemanner; the release profile can be manipulated or tailored so that avariety of retarded release profiles can be provided for the sameformulation. Control of the release profile with the dosage form of thepresent invention can be achieved for dosage forms designed forimmediate release or dosage forms designed for retarded (sustained)release. It is also an advantage that it is no longer necessary to relyon the choice and amount of hydrophilic polymer(s) to modify thedissolution profile of a retarded release formulation which in variouscircumstances has proven to not even be possible under realisticconditions.

It has also been surprisingly found that by modifying the outer shape ofthe pharmaceutical dosage form the release profile may be modifiedwithout simultaneously diminishing the breaking strength of thepharmaceutical dosage form. In particular, it has been surprisinglyfound that in spite of a modified outer shape of the pharmaceuticaldosage form which causes a certain degree of fragility, the overalltamper resistance of the pharmaceutical dosage form can be maintained.

Furthermore, it has been surprisingly found that by modifying the outershape of the pharmaceutical dosage form the storage stability, e.g. thestorage stability of the release profile, can be increased compared toconventional dosage forms having a comparable release profile beforestorage.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A) is a schematic top view of a tablet of the invention. FIG. 1B)is a cross-sectional view along A-A of the tablet of FIG. 1A).

FIG. 2A) is a schematic top view of another embodiment of the tablet ofthe invention. FIG. 2B) is a cross-sectional view along A-A of thetablet of FIG. 2A).

FIG. 3A) is a schematic top view of another embodiment of a tablet ofthe invention. FIG. 3B) is a cross-sectional view along line A-A of thetablet of FIG. 3A). FIG. 3C) is a cross-sectional side view along B-B ofthe tablet of FIG. 3A).

FIG. 4A) is a schematic top view of another embodiment of a tablet ofthe invention. FIG. 4B) is a cross-sectional view along line A-A of thetablet of FIG. 4A). FIG. 4C) is a cross-sectional side view along B-B ofthe tablet of FIG. 4A).

FIG. 5A) is a schematic top view of another embodiment of a tablet ofthe invention. FIG. 5B) is a cross-sectional view along line A-A of thetablet of FIG. 5A). FIG. 5C) is a cross-sectional side view along B-B ofthe tablet of FIG. 5A).

FIG. 6 is a schematic top view of another embodiment of the tablet ofthe invention. FIG. 6B) is a cross-sectional view along A-A of thetablet of FIG. 6A). FIG. 6C) is a cross-sectional side view along B-B ofthe tablet of FIG. 6A).

FIG. 7A) is a schematic view of a conventional oblong tablet. FIG. 7B)is a schematic view of an embodiment of a pharmaceutical dosage formaccording to the invention having an increased ratio of surface tovolume and surface to weight, respectively, achieved by a taper right inthe middle of the pharmaceutical dosage form.

FIG. 8A) is a schematic view of a preferred pharmaceutical dosage formaccording to the invention having two recesses on opposing sides (“innercourtyards”). FIG. 8B) is a schematic view of the cross-section of thepharmaceutical dosage form depicted in FIG. 8A) showing that the face ofthe cross-section assumes the shape of a H.

FIG. 9A) is a schematic view of the cross-sectional face of thepharmaceutical dosage form depicted in FIG. 8A). FIG. 9B) is a schematicview of the cross-sectional face of a pharmaceutical dosage formaccording to the invention that is similar to the cross-sectional faceof the pharmaceutical dosage form depicted in FIG. 9A). FIG. 9C) is aschematic view of the cross-sectional face of a pharmaceutical dosageform according to the invention that is similar to the cross-sectionalface of pharmaceutical dosage forms depicted in FIGS. 9A) and 9B).

FIG. 10 is a schematic view of a particularly preferred pharmaceuticaldosage form according to the invention. FIG. 10A) is a top view, FIG.10B) is a side view.

FIG. 11 is a schematic view of a conventional pharmaceutical dosage formcomprising a cylindrical central element (53) and two spherical caps (54a) and (54 b).

FIG. 12 is a schematic view of a cross-section of a preferredpharmaceutical dosage form divided into voxels (55) of identical volumeand surface to roughly estimate the overall surface of the dosage form.

FIG. 13 is a schematic view of pharmaceutical dosage forms according tothe invention. The pharmaceutical dosage form depicted in FIG. 13A)assumes the shape of a cross, the pharmaceutical dosage form depicted inFIG. 13B) assumes the shape of a star.

FIG. 14 is a schematic view of various pharmaceutical dosage formsaccording to the invention. The pharmaceutical dosage form depicted inFIG. 14A) assumes the shape of an eight, the pharmaceutical dosage formdepicted in FIG. 14B) assumes the shape of a flattened peanut, thepharmaceutical dosage form depicted in FIG. 14C) assumes the shape of aparallel double cylinder, the pharmaceutical dosage form depicted inFIG. 14D) assumes the shape of a parallel double tube, thepharmaceutical dosage form depicted in FIG. 14E) assumes the shape of asquare with a round hole in the middle, and the pharmaceutical dosageform depicted in FIG. 14F) assumes the shape of a wavy or corrugateditem.

FIG. 15 is a schematic view of pharmaceutical dosage forms according tothe invention. The pharmaceutical dosage form depicted in FIG. 15A)assumes the shape of a short tube, the pharmaceutical dosage formdepicted in FIG. 15B) assumes the shape of a ring.

FIG. 16 is a schematic view of pharmaceutical dosage forms according tothe invention. The pharmaceutical dosage form depicted in FIG. 16A)assumes the shape of a triangle with two recesses on opposing sides, thepharmaceutical dosage form depicted in FIG. 16B) assumes the shape of apentagon with two recesses on opposing sides.

FIG. 17 is a schematic view of the cross-sectional face of the preferredpharmaceutical dosage form depicted in FIG. 10. In FIG. 17A) the maximumextension (56) of the dosage form orthogonal to the main area ofextension (57) of the dosage form is spaced from the centre of mass (58)of the dosage form parallel to said main area of extension (57). In FIG.17B) the centre of mass (58) is surrounded by concentric rings (60 a) to(60 d) indicating increasing distances from the centre of mass.

FIG. 18 is a schematic view of the pharmaceutical dosage form shown inFIG. 10 and the set-up for measuring the breaking strength in directionsof extension E₁, E₂ and E₃, respectively. FIG. 18A) shows how thepharmaceutical dosage form should be placed between the two plain jaws(61 a) and (61 b) of the measuring device in order to measure thebreaking strength in direction of extension E₁. FIG. 18B) shows how thepharmaceutical dosage form should be placed between the two plain jaws(61 a) and (61 b) of the measuring device in order to measure thebreaking strength in direction of extension E₂. FIG. 18C) shows how thepharmaceutical dosage form should be placed between the two plain jaws(61 a) and (61 b) of the measuring device in order to measure thebreaking strength in direction of extension E₃.

FIG. 19 is a preferred embodiment of the measuring system that is usedin order to measure the breaking strength of the pharmaceutical dosageform according to the invention. The two jaws (61 a) and (61 b) of thismeasuring system are not plain, but contain an embossment (62) and acavity (63, 64), respectively. FIG. 19A) shows a schematic view of jaw(61 a) containing embossment (62) and jaw (61 b) containing indentation(63/64). FIG. 19B) shows a schematic view of jaws (61 a) and (61 b) onfaces (65 a) and (65 b), respectively.

FIG. 20A) shows how the pharmaceutical dosage form shown in FIG. 10should be placed between the two jaws (61 a) and (61 b) of the measuringdevice shown in FIG. 19 in order to measure the breaking strength indirection of extension E₁. FIG. 20B) shows how the pharmaceutical dosageform should be placed between the two jaws (61 a) and (61 b) of themeasuring device in order to measure the breaking strength in directionof extension E₂. FIG. 20C) shows how the pharmaceutical dosage formshould be placed between the two jaws (61 a) and (61 b) of the measuringdevice in order to measure the breaking strength in direction ofextension E₃.

FIG. 21 shows the release profile of the tablet according to inventiveexample 1-2 (H-shape) and of the tablet according to comparative exampleC-1 (oblong) immediately after manufacture.

FIG. 22 shows the release profile of the tablet according to inventiveexample 1-1 (H-shape) and of the tablet according to inventive example1-2 (H-shape).

FIG. 23 shows the release profile of the tablet according to comparativeexample C-1 (oblong) before and after storage under various conditions(40° C., 6 months; 25° C., 9 months; and 30° C., 9 months,respectively).

FIG. 24 shows that the release profile of the tablet according toinventive example 1-2 (H-shape) before and after storage under variousconditions (40° C., 6 months; 25° C., 9 months; and 30° C., 9 months,respectively).

DETAILED DESCRIPTION OF THE INVENTION

Unless expressly stated otherwise, any preferred embodiment of theinvention that will be described in connection with a particular aspectof the invention hereinafter shall also apply to the other aspects ofthe invention. In this regard, embodiments that have been described interms of key words that are synonymous to or at least partially overlapwith similar key words mentioned elsewhere in the specification, such as“pharmaceutically active ingredient” and “pharmacologically activecompound (A)”, or “pharmaceutical dosage form” and “tablet”, shall beunderstood as being also applicable in terms of said similar key words.

A first aspect of the invention relates to a pharmaceutical dosage form,especially an oral dosage form, particularly a tablet, comprising atleast one pharmaceutically active ingredient, and having a shapecomprising a longitudinal axis and two opposite longitudinal edges, atransversal axis perpendicular to the longitudinal axis and two oppositetransversal edges, a front side, an opposite back side and acircumferential rim between said front and back side, wherein the frontside and/or the back side comprise a basis area and wherein the frontside and/or the back side comprise at least one bulge which extendsabove said basis area, said at least one bulge being present at and/oradjacent to at least a section of one or both longitudinal edges and/orat and/or adjacent to at least a section of one or both transversaledges and/or between both longitudinal edges and both transversal edges.The front side and/or the back side of the dosage form, in particularthe basis area of the front side and/or the basis area of the back side,can further comprise at least one indentation.

Although it is also possible that the longitudinal axis and thetransversal axis of the tablet have essentially the same length, it ispreferred that the tablet of the invention has a longitudinal axis beinglonger than its transversal axis. That is, preferred embodiments of thetablet of the invention exhibit an oblong shape. The longitudinal axisis typically extending through the middle part of the tablet betweenboth opposing longitudinal edges from one transversal edge to theopposite transversal edge, in particular in such a way that its lengthis maximized. The transversal axis is typically extending from onelongitudinal edge to the opposite longitudinal edge, in particular insuch a way that its length is maximized. The transversal axis isoriented perpendicular to the longitudinal axis.

The basis area of the front side and/or the back side of the tablet ofthe invention does not necessarily have to be flat, but can in oneembodiment exhibit an irregular or regular three dimensional pattern,which, however, is not extending to any significant degree towards thedimension of a bulge or an indentation.

The average distance between the front basis area and the back basisarea of one embodiment of the tablet of the invention usually is smallerthan the length of its transversal axis. Those opposite sides of thetablet which have the smallest average distance are usually comprisingthe front and the back basis areas.

According to another preferred embodiment, a tablet is provided, whereinthe front side and the back side each comprise at least one bulge atleast along a section at and/or adjacent to both longitudinal edgesand/or at least along a section at and/or adjacent to both transversaledges. In this respect it is even more preferred in certain cases thatsaid front side and said back side comprise an at least essentiallycontinuous bulge at and/or adjacent to at least two third of bothopposite longitudinal edges and/or at and/or adjacent to at least twothird of both opposite transversal edges.

The bulge may have any geometric cross-section, and can, for example, berounded or can have a rectangular, triangular or square cross-section.The bulges preferably have a width which is less than half the width,more preferably less than one third of the width of the tablet. Thelength of the bulges can vary to a great extent. It is preferred thatthe overall length of an individual bulge is at least one half of thelength of the longitudinal edge or of the transversal edge, depending onits location. Typically, the overall length of a bulge is much longerthan its width, e.g. several times the width of the bulge, such as morethan 2, 3, 4, 5 or 6 times of its width, in particular when oriented inthe longitudinal direction, or more than 2, 3 or 4 times of its width,in particular when oriented in the transversal direction. A bulge in themeaning of the present invention shall also comprise a series ofadjacent bulge portions. These bulge portions, when viewed from above,can, for example, have the circumferential form of a circle, an oval, arectangle, a square, a triangle or any other polygonal form, or may comeclose to these forms, or may even have an irregular form.

A bulge which is located at a longitudinal and/or at a transversal edgeregularly passes over from the circumferential rim of the tablet withouta significant transition zone or transition step, i.e. without a “land”.In such an embodiment there is a smooth transition from the rim part tothe bulge part so that the outer surfaces of the rim and the bulge forma continuous surface at least over a section. A bulge which ispositioned adjacent to a longitudinal or adjacent to a transversal edgeis in contrast thereto not directly placed at the circumferential rim ofthe tablet but is separated from the rim in the plane of the basis areaby a portion, in particular a minor portion, which can be attributed tobe part of the basis area. Said minor portion is known in the field oftablet technology as “the land”. This minor area usually has a widthbeing smaller than the average width of the bulge itself. In a preferredembodiment, the land is in the range from about 0.05 mm to about 0.5 mm,e.g. about 0.1 mm.

In a particularly suitable embodiment, the tablet of the invention isprovided with bulges at both longitudinal edges and/or both transversaledges of both the front side and the back side of the tablet, whereinthese bulges extend at least over one half, more preferably over twothirds of the length of the longitudinal and/or transversal edges, evenmore preferably over the whole length of the longitudinal and/ortransversal edges. In another preferred embodiment, the bulgescontinuously circumscribe the basis area of the front side and/or theback side, preferably the front and the back side, at and/or adjacent tothe respective longitudinal and transversal edges. Most desirableresults in terms of an improved release profile can for example beobtained with tablets of the invention having bulges at bothlongitudinal edges of both sides of the tablet. The cross-section ofthese tablets can be described to have or come close to an H-shape. Byuse of the expression H-shape it shall just be indicated that a tabletbody having opposite, in particular rather flat, basis areas is providedwith opposing bulges at the longitudinal edges on both sides of thetablet body. For example, in one H-shape embodiment the bulges canprotrude above their respective basis areas only to a minor extentcompared to the lateral distance between the bulges along oppositelongitudinal edges, e.g. up to about 1 or 2 mm.

In one preferred embodiment, a tablet of the invention, in particularits oblong form, comprises at or adjacent to, in particular adjacent to,major portions of both opposite longitudinal edges, in particular atleast along two thirds of the longitudinal edges, of the front side atleast one bulge. In another preferred embodiment, a tablet of theinvention, in particular its oblong form, comprises at least one bulgeat or adjacent to, in particular adjacent to, major portions of bothopposite longitudinal edges, in particular at least along two thirds ofthe longitudinal edges, of both the front side and the back side of thetablet. In another preferred embodiment, the tablet of the invention, inparticular its oblong form, comprises a circumferential bulge at oradjacent to, in particular adjacent to, the circumferential edge of thefront side of said tablet. In another preferred embodiment, the tabletof the invention, in particular its oblong form, comprises acircumferential bulge at or adjacent to, in particular adjacent to, thecircumferential edge of both the front side and the back side of saidtablet.

According to another suitable embodiment of the tablet of the invention,it is provided that one or both longitudinal edges are essentiallystraight over at least a major part of their length and/or wherein oneor both transversal edges are curved over a major part of their length,in particular curved in the form of an essentially circular arc. It isof course also possible that the longitudinal edges exhibit any otherirregular or regular shape, for example, having a wave-like edge portionat least over a section. It is also possible that the transversal edgeexhibits the shape of a triangle or any other polygonal shape. Ingeneral, both longitudinal and transversal edges form the circumferenceof the front side and the back side of the tablet.

For most applications it is sufficient that the longitudinal length,that is, the length of the longitudinal axis, of the tablet does notexceed 30 mm.

According to another embodiment, the tablet of the invention preferablyhas an average thickness over the basis areas of the front and the backside of at least about 1 mm, and in particular of no more than about 6mm, more in particular ranging from about 1 mm to about 3 mm or more inparticular ranging from about 2 mm to about 4 mm.

According to one embodiment of the tablet of the invention, the bulgeextends perpendicular from the basis area of the front side and/or fromthe basis area of the back side in average from about 0.5 mm to about 2mm, in particular from about 0.5 mm to about 1 mm.

Tablets of the invention preferably have a length in the longitudinaldirection in the range of about 5 mm to about 30 mm, in particular inthe range of about 15 mm to about 25 mm, more in particular about 17 mmto about 23 mm, even more in particular about 21 mm; a width in therange of about 5 mm to about 15 mm, in particular in the range of about7 mm to about 12 mm, more in particular about 7 mm to about 10 mm, evenmore in particular 7 mm, 9 mm or 10 mm; and a thickness over the basisareas in the range of about 1 mm to about 6 mm, in particular in therange of about 1.5 mm to about 4 mm, even more in particular from 2 mmto about 4 mm, even further in particular from about 2.5 mm to about 3.5mm.

As indicated above, the front side and/or the back side of the tablet ofthe invention, in particular the basis area of the front side and/or thebasis area of the back side, can in one embodiment further comprise atleast one indentation. As has been found, this generally allows for afurther improvement of the control of the release profile. Theindentation in general in one embodiment represents a hollow space whichis provided or embedded in the overall surface of the tablet. Forexample, the front side, the back side, in particular the basis areas ofthe front side and/or the back side, the rim and/or at least one bulgecan be provided with at least one indentation.

Indentations, when viewed from above, can have any irregular or regularshape, for example, the form of a square, rectangle, triangle, oval orcircle. In one embodiment the indentations can take the form of acylinder, a cube, a cuboid or a half-sphere, that is the walls and theopening forming the indentation come close to describing the form of acylinder, a cube, a cuboid or a half-sphere. When viewed from above, thesilhouette shape of the indentations has essentially the same width andlength dimensions. It is also possible that when viewed from above, thesilhouette shape of an indentation has a longer length dimension than awidth dimension, for example, a length dimension which is at least 2, 3or 4 times the width dimension. Accordingly, when viewed from above, thesilhouette shape can be rather elongate, e.g. a rectangle, and can havea regular silhouette form, e.g. straight, wave-like, or zig-zag, or canbe rather irregular. In another embodiment an array of indentations canbe formed, for example on the front side and/or the back side. For manyapplications it has been found to be sufficient that when viewed fromabove, the silhouette-shape of the indentation has a length dimensionwhich is essentially identical to its width dimension as, for example,can be found with a circular, square-like or slightly oval or slightlyrectangular shape. Said width dimension of the indentations, which isregularly determined parallel to the transversal axis, usually is lessthan one half of the transversal length of the tablet, in particularless than one third of the transversal length of the tablet. In oneembodiment the width dimension is essentially identical to the depth ofthe indentation or is no more than 2 or 3 times the depth of theindentation. The length dimension of the indentation, which is regularlydetermined parallel to the longitudinal axis, usually is no longer thanthree quarters of the longitudinal length of the tablet, in particularno longer than one half of the longitudinal length of the tablet, andpreferably no longer than one third of the longitudinal length of thetablet. A hole in a tablet is not an indentation in the meaning of thepresent invention. The silhouette shape and the depth of saidindentations can vary depending on the desired release profile. Usuallycare should be taken that the depths of these indentations does not cometoo close to the thickness of the tablet in order to prevent that uponhandling a hole through the tablet will be formed. Preferably theindentations have a depth which does not go beyond half the thickness ofthe tablets of the invention. For most applications it is frequentlyalready sufficient that the maximum depth of said indentations does notgo beyond one third of the thickness of the tablet of the invention. Theaverage thickness of the tablet of the invention in general isdetermined as the distance between the front and back side of the tabletor preferably between the basis area of the front side and the basisarea of the back side.

By using the expressions front side and back side it shall be indicatedthat the tablet of the invention has two opposite sides which each canbe provided with bulges and/or indentations. In consequence, theselection of which is the front side and which is the back side israther arbitrary. Accordingly, the expressions front side and back sidecould also be replaced by first side and opposite second side,respectively.

In one embodiment of the invention, there is provided a tablet whereinthe front side and/or the back side, in particular the, in particularessentially flat, basis area of the front side and/or the, in particularessentially flat, basis area of the back side, comprise in addition toat least one bulge at least one indentation, in particular betweenopposite longitudinal and/or transversal bulges.

In one embodiment of the invention it is provided that both the frontand the back side comprise at least one indentation.

The indentations on the front side and on the back side of the tablet ofthe invention can at least once be at least partially off-set or can atleast once be positioned in a congruent manner. In one preferredembodiment, all the indentations of the front side and all indentationson the back side are at least partially off-set or are positioned in acongruent manner.

The indentations are regularly positioned in the basis area of the frontand/or the back side of the tablet of the invention. It is for examplepossible to place two or more of such indentations adjacent to eachother, e.g. in a row located between the longitudinal edges of the frontand/or the back side. The indentations are preferably located betweenopposite longitudinally extending bulges at or adjacent to thelongitudinal edges of the front and/or the back side of the tablet ofthe invention.

In one preferred embodiment, a tablet of the invention, in particularits oblong form, comprises at or adjacent to, in particular adjacent to,major portions of both longitudinal edges, in particular at least alongtwo thirds of the longitudinal edges of the front side at least onebulge, and, in particular between the bulges along opposite longitudinaledges, at least one indentation.

In another preferred embodiment, a tablet of the invention, inparticular its oblong form, comprises at least one bulge at or adjacentto, in particular adjacent to, major portions of both oppositelongitudinal edges, in particular at least along two thirds of thelongitudinal edges of both the front side and the back side of thetablet as well as at least one indentation on the front side and/or theback side, in particular on the basis area of the front side and/or thebasis of the back side, of the tablet, in particular between the bulgeswhich are located along opposite longitudinal edges on the front sideand/or the back side, respectively. In another preferred embodiment, thetablet of the invention, in particular its oblong form, comprises acircumferential bulge at or adjacent to, in particular adjacent to, thecircumferential edge of the front side and/or back side of said tablet,and at least one indentation on the front side and/or back side, inparticular on the basis area circumscribed by the circumferential bulgeon the front and/or on the back side. In another preferred embodiment,the tablet of the invention, in particular its oblong form, comprises acircumferential bulge at or adjacent to, in particular adjacent to, thecircumferential edge of both the front side and the back side of saidtablet and at least one indentation on the front side and the back side,in particular on the basis area circumscribed by the circumferentialbulge of the front side and on the basis area circumscribed by thecircumferential bulge of the back side.

There are generally no limitations as to the pharmaceutically activeingredient(s) which can be incorporated into the tablet of theinvention.

Suitable active ingredients are those which exert a local physiologicaleffect, as well as those which exert a systemic effect, after oraladministration. Examples of suitable active ingredients encompass:

analgesic and anti-inflammatory drugs (NSAIDs, fentanyl, indomethacin,ibuprofen, ketoprofen, nabumetone, paracetamol, piroxicam, tramadol,COX-2 inhibitors such as celecoxib and rofecoxib);anti-arrhythmic drugs (procainamide, quinidine, verapamil);antibacterial and antiprotozoal agents (amoxicillin, ampicillin,benzathine penicillin, benzylpenicillin, cefaclor, cefadroxil,cefprozil, cefuroxime axetil, cephalexin, chloramphenicol, chloroquine,ciprofloxacin, clarithromycin, clavulanic acid, clindamycin,doxyxycline, erythromycin, flucloxacillin sodium, halofantrine,isoniazid, kanamycin sulphate, lincomycin, mefloquine, minocycline,nafcillin sodium, nalidixic acid, neomycin, norfloxacin, ofloxacin,oxacillin, phenoxymethyl-penicillin potassium,pyrimethamine-sulfadoxime, streptomycin, TMC207);anti-coagulants (warfarin);antidepressants (amitriptyline, amoxapine, butriptyline, clomipramine,desipramine, dothiepin, doxepin, fluoxetine, reboxetine, amineptine,selegiline, gepirone, imipramine, lithium carbonate, mianserin,milnacipran, nortriptyline, paroxetine, sertraline;3-[2-[3,4-dihydrobenzofuro[3,2-c]pyridin-2(1H)-yl]ethyl]-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one);anti-diabetic drugs (glibenclamide, metformin);anti-epileptic drugs (carbamazepine, clonazepam, ethosuximide,gabapentin, lamotrigine, levetiracetam, phenobarbitone, phenyloin,primidone, tiagabine, topiramate, valpromide, vigabatrin);antifungal agents (amphotericin, clotrimazole, econazole, fluconazole,flucytosine, griseofulvin, itraconazole, ketoconazole, miconazolenitrate, nystatin, terbinafine, voriconazole);antihistamines (astemizole, cinnarizine, cyproheptadine,decarboethoxyloratadine, fexofenadine, flunarizine, levocabastine,loratadine, norastemizole, oxatomide, promethazine, terfenadine);anti-hypertensive drugs (captopril, enalapril, ketanserin, lisinopril,minoxidil, prazosin, ramipril, reserpine, terazosin);anti-muscarinic agents (atropine sulphate, hyoscine);antineoplastic agents and antimetabolites (platinum compounds, such ascisplatin, carboplatin; taxanes, such as paclitaxel, docetaxel; tecans,such as camptothecin, irinotecan, topotecan; vinca alkaloids, such asvinblastine, vindecine, vincristine, vinorelbine; nucleoside derivativesand folic acid antagonists such as 5-fluorouracil, capecitabine,gemcitabine, mercaptopurine, thioguanine, cladribine, methotrexate;alkylating agents, such as the nitrogen mustards, e.g. cyclophosphamide,chlorambucil, chlormethine, iphosphamide, melphalan, or thenitrosoureas, e.g. carmustine, lomustine, or other alkylating agents,e.g. busulphan, dacarbazine, procarbazine, thiotepa; antibiotics, suchas daunorubicin, doxorubicin, idarubicin, epirubicin, bleomycin,dactinomycin, mitomycin; HER 2antibody, such as trastuzumab;podophyllotoxin derivatives, such as etoposide, teniposide; farnesyltransferase inhibitors; anthrachinon derivatives, such as mitoxantron);anti-migraine drugs (alniditan, naratriptan, sumatriptan);anti-Parkinsonian drugs (bromocryptine mesylate, levodopa, selegiline);antipsychotic, hypnotic and sedating agents (alprazolam, buspirone,chlordiazepoxide, chlorpromazine, clozapine, diazepam, flupenthixol,fluphenazine, flurazepam, 9-hydroxyrisperidone, lorazepam, mazapertine,olanzapine, oxazepam, pimozide, pipamperone, piracetam, promazine,risperidone, selfotel, seroquel, sertindole, sulpiride, temazepam,thiothixene, triazolam, trifluperidol, ziprasidone, zolpidem);anti-stroke agents (lubeluzole, lubeluzole oxide, riluzole, aptiganel,eliprodil, remacemide);antitussive (dextromethorphan, laevodropropizine);antivirals (acyclovir, ganciclovir, loviride, tivirapine, zidovudine,lamivudine, zidovudine+lamivudine, didanosine, zalcitabine, stavudine,abacavir, lopinavir, amprenavir, nevirapine, efavirenz, delavirdine,indinavir, nelfinavir, ritonavir, saquinavir, adefovir, hydroxyurea,TMC120, TMC125, TMC278);beta-adrenoceptor blocking agents (atenolol, carvedilol, metoprolol,nebivolol, propanolol);cardiac inotropic agents (aminone, digitoxin, digoxin, milrinone);corticosteroids (beclomethasone dipropionate, betamethasone, budesonide,dexamethasone, hydrocortisone, methylprednisolone, prednisolone,prednisone, triamcinolone); disinfectants (chlorhexidine);diuretics (acetazolamide, frusemide, hydrochlorothiazide, isosorbide);enzymes;essential oils (anethole, anise oil, caraway, cardamom, cassia oil,cineole, cinnamon oil, clove oil, coriander oil, dementholised mint oil,dill oil, eucalyptus oil, eugenol, ginger, lemon oil, mustard oil,neroli oil, nutmeg oil, orange oil, peppermint, sage, spearmint,terpineol, thyme);gastro-intestinal agents (cimetidine, cisapride, clebopride,diphenoxylate, domperidone, famotidine, lansoprazole, loperamide,loperamide oxide, mesalazine, metoclopramide, mosapride, nizatidine,norcisapride, olsalazine, omeprazole, pantoprazole, perprazole,prucalopride, rabeprazole, ranitidine, ridogrel, sulphasalazine);haemostatics (aminocaproic acid);lipid regulating agents (atorvastatin, lovastatin, pravastatin,probucol, simvastatin);local anaesthetics (benzocaine, lignocaine);opioid analgesics (buprenorphine, codeine, dextromoramide,dihydrocodeine, hydrocodone, oxycodone, morphine);parasympathomimetics and anti-dementia drugs (ATT-082, eptastigmine,galanthamine, metrifonate, milameline, neostigmine, physostigmine,tacrine, donepezil, rivastigmine, sabcomeline, talsaclidine, xanomeline,memantine, lazabemide);peptides and proteins (antibodies, becaplermin, cyclosporine,erythropoietin, immunoglobulins, insuline);sex hormones (oestrogens; conjugated oestrogens, ethinyloestradiol,mestranol, oestradiol, oestriol, oestrone; progestogens; chlormadinoneacetate, cyproterone acetate, 17-deacetyl norgestimate, desogestrel,dienogest, dydrogesterone, ethynodiol diacetate, gestodene, 3-ketodesogestrel, levonorgestrel, lynestrenol, medroxy-progesterone acetate,megestrol, norethindrone, norethindrone acetate, norethisterone,norethisterone acetate, norethynodrel, norgestimate, norgestrel,norgestrienone, progesterone, quingestanol acetate);stimulating agents (sildenafil);vasodilators (amlodipine, buflomedil, amyl nitrite, diltiazem,dipyridamole, glyceryl trinitrate, isosorbide dinitrate, lidoflazine,molsidomine, nicardipine, nifedipine, oxpentifylline, pentaerythritoltetranitrate); their N-oxides, their pharmaceutically acceptable acid orbase addition salts and their stereochemically isomeric forms.

Pharmaceutically acceptable acid addition salts comprise the acidaddition salt forms which can conveniently be obtained by treating thebase form of the active ingredient with appropriate organic andinorganic acids. Active ingredients containing an acidic proton may beconverted into their non-toxic metal or amine addition salt forms bytreatment with appropriate organic and inorganic bases. The termaddition salt also comprises the hydrates and solvent addition formswhich the active ingredients are able to form. Examples of such formsare e.g. hydrates, alcoholates and the like. The N-oxide forms of theactive ingredients comprise those active ingredients wherein one orseveral nitrogen atoms are oxidized to the so-called N-oxide.

The active ingredient(s) is (are) present in the dosage form in atherapeutically effective amount. The amount that constitutes atherapeutically effective amount varies according to the ingredientsbeing used, the condition being treated, the severity of said condition,the patient being treated, and whether the dosage form is designed foran immediate or retarded release. The amount of active ingredient(s)used in the present invention preferably ranges from about 0.01% toabout 90% (w/w), in particular from about 0.01% to about 50% (w/w), morein particular from about 20% to about 50% (w/w).

Unless explicitly stated otherwise, in the meaning of the presentinvention the indication “w/w” shall mean weight of the compoundspecified per total weight of the composition forming the tablet.

In one embodiment, the one or more active ingredients are incorporatedin a tablet for immediate release.

In another embodiment, the one or more active ingredients areincorporated in a tablet for retarded release. In this case, the activeingredient(s) of the tablet of the invention is (are) conventionallyembedded in conventional formulating aids and/or one or more hydrophilicpolymers. These hydrophilic polymers tend to swell upon contact withaqueous fluids following administration, and result in a viscous, drugrelease regulating gel layer. Preferably the viscosity of these polymersranges from 150 to 100.000 mPa·s (apparent viscosity of a 2% aqueoussolution at 20° C.). Examples of suitable hydrophilic polymers include:

-   -   alkylcelluloses, such as, methylcellulose;    -   hydroxyalkylcelluloses, for example, hydroxymethylcellulose,        hydroxyethylcellulose, hydroxypropylcellulose and        hydroxybutylcellulose;    -   hydroxyalkyl alkylcelluloses, such as, hydroxyethyl        methylcellulose and hydroxypropyl methylcellulose;    -   carboxyalkylcelluloses, such as, carboxymethylcellulose;    -   alkali metal salts of carboxyalkylcelluloses, such as, sodium        carboxymethylcellulose;    -   carboxyalkylalkylcelluloses, such as,        carboxymethylethylcellulose;    -   carboxyalkylcellulose esters;    -   other natural, semi-synthetic, or synthetic polysaccharides,        such as, alginic acid, alkali metal and ammonium salts thereof,        carrageenans, galactomannans, tragacanth, agar-agar, gummi        arabicum, guar gummi, xanthan gummi, starches, pectins, such as        sodium carboxymethylamylopectin, chitin derivates such as        chitosan, polyfructans, inulin; polyacrylic acids and the salts        thereof;    -   polymethacrylic acids and the salts thereof, methacrylate        copolymers;    -   polyvinylalcohol;    -   polyvinylpyrrolidone, copolymers of polyvinylpyrrolidone with        vinyl acetate;    -   combinations of polyvinylalcohol and polyvinylpyrrolidone;    -   polyalkylene oxides such as polyethylene oxide and polypropylene        oxide and copolymers of ethylene oxide and propylene oxide.

Preferably the one or more hydrophilic polymers are cellulosederivatives, in particular cellulose ether derivatives, such as forexample alkylcelluloses or hydroxyalkylcelluloses or hydroxyalkylalkylcelluloses, more in particular hydroxyalkylcelluloses orhydroxyalkyl alkylcelluloses.

Most preferred cellulose ether derivatives are hydroxypropylmethylcellulose (HMPC) and hydroxypropyl cellulose (HPC). Differentviscosity grades of hydroxypropyl cellulose and hydroxypropylmethylcellulose are commercially available. Hydroxypropylmethylcellulose preferably used in the present invention has a viscositygrade ranging from about 3,500 mPa·s to about 100,000 mPa·s, inparticular ranging from about 4,000 mPa·s to about 20,000 mPa·s and mostin particular a viscosity grade of about 6,500 mPa·s to about 15,000mPa·s (apparent viscosity of a 2% aqueous solution at 20° C.), e.g.hypromellose 2208 (DOW, Antwerp, Belgium). Hydroxypropyl cellulosehaving a viscosity lower than 1,500 mPa·s (apparent viscosity of a 2%aqueous solution at 20° C.) is preferred, in particular hydroxypropylcellulose having a viscosity in the range from about 150 to about 700mPa·s, preferably from 200 to 600 mPa·s, e.g. Klucel EF (Hercules,Wilmington, USA).

Preferably, the amount of viscous hydrophilic polymers, in particularHPMC and HPC, in the present formulation ranges from about 0.01 to about80% (w/w), in particular from about 10 to about 60% (w/w), more inparticular between 30 and 60% (w/w).

In addition to the one or more hydrophilic polymers, the retardedrelease formulation can in one embodiment comprise pregelatinizedstarch. The amount of pregelatinized starch preferably is in the rangefrom 5 to 80% (w/w), in particular from 5 to 15% (w/w).

In one embodiment, the tablet of the invention comprises at least onepharmaceutically active ingredient, pregelatinized starch, and HPCand/or HPMC, in particular at least one pharmaceutically activeingredient, pregelatinized starch, HPC and HPMC.

The tablets according to the invention are preferably prepared by way ofcompression using a die and a punch.

The tablets of the invention can optionally be provided, partially orcompletely, with a conventional tablet coating. The tablets of thepresent invention are preferably film coated with art-known film coatingcompositions. The coating is applied to improve the aesthetic impressionand/or the taste of the tablets and the ease with which they can beswallowed. Coating the tablets of the present invention can also serveother purposes, e.g. improving stability and shelf-life. Suitablecoating formulations comprise a film forming polymer such as, forexample, hydroxypropyl methylcellulose, e.g. hypromellose 2910 (5mPa·s), a plasticizer such as, for example, a glycol, e.g. propyleneglycol or polyethylene glycol, an opacifier, such as, for example,titanium dioxide, and a film smoothener, such as, for example, talc.Suitable coating solvents are water as well as organic solvents.Examples of organic solvents are alcohols, e.g. ethanol or isopropanol,ketones, e.g. acetone, or halogenated hydrocarbons, e.g. methylenechloride. Optionally, the coating can contain a therapeuticallyeffective amount of one or more active ingredients to provide for animmediate release of said active ingredient(s) and thus for an immediaterelief of the symptoms treated by said active ingredient(s). Coatedtablets of the present invention are prepared by first making the tabletcores in the way as described above and subsequently coating said tabletcores using conventional techniques, such as coating in a coating pan.For example, PEG, e.g. PEG 20.000, or HPMC can be used for the coating.

Beside active ingredient(s) and optional hydrophilic polymers, thetablet of the present invention can also optionally comprisepharmaceutically acceptable formulation agents such as fillers,glidants, binding agents, granulating agents, anti-caking agents,lubricants, flavors, dyes, and preservatives.

The filler may be selected from soluble fillers, for example, sucrose,lactose, trehalose, maltose, mannitol, sorbitol, inulin, and frominsoluble fillers, for example, dicalcium or tricalcium phosphate, talc.An interesting filler is lactose, in particular, lactose monohydrate.Different grades of lactose can be used. One type of lactose preferablyused in the present invention is lactose monohydrate 200 mesh (DMV,Veghel, the Netherlands). Another lactose monohydrate, lactosemonohydrate of the type DCL 11 (DMV, Veghel, the Netherlands), can alsopreferably be used. The notation DCL refers to “Direct CompressionLactose”. The number 11 is a reference number of the manufacturer. Thistype of lactose is characterised in that 98% (w/w) of the particles,based on the total amount of lactose employed, have a diameter smallerthan 250 μm, 30% (w/w) to 60% (w/w) of the particles, based on the totalamount of lactose employed, have a diameter of 100 μm, and at maximum15% (w/w) of the particles, based on the total amount of lactoseemployed, have a diameter of smaller than 45 μm. The weight percentageof filler ranges between about 6% and about 54% (w/w).

Among the optional formulating agents that further can be comprised inthe present formulation there can be mentioned agents such aspolyvidone; starch; acacia gum; gelatin; seaweed derivatives, e.g.alginic acid, sodium and calcium alginate; cellulose derivatives, e.g.ethylcellulose, hyoroxypropyl methylcellulose, having useful binding andgranulating properties; glidants such as colloidal silica, starch ortalc; lubricants such as magnesium stearate and/or palmitate, calciumstearate, stearic acid, polyethylene glycol, liquid paraffin, sodium ormagnesium lauryl sulphate; anti-adherents such as talc and corn starch.

The first aspect of the present invention can be more readily understoodby reference to FIGS. 1-6.

In FIG. 1A) a tablet 1 is depicted showing its front side 2 from thetop. The tablet 1 has a longitudinal axis 4 in the longitudinaldirection and a transversal axis 6, perpendicular thereto, in thetransversal direction. The two opposing longitudinal edges 8 and 10 andthe two opposing transversal edges 12 and 14 are forming thecircumference of the front side 2 of the tablet 1. In the depictedembodiment the longitudinal edges 8, 10 are essentially straight whereasthe transversal edges 12, 14 are rounded. Tablet 1 of FIG. 1A) has acircumferential bulge 16, 20 on both the upper side 2 and the lower side18 (FIG. 1B)) having reference sign 20. The bulges 16 and 20 arepositioned adjacent to the longitudinal and transversal edges and raiseabove the basis area 22 of the front side 2, and above the basis area 24of the back side 18, respectively. In the embodiment shown in FIG. 1A),1B) the basis areas 22, 24 have a transversal width “a” which is smallerthan the transversal width “b” of the bulges.

In FIG. 2A) tablet 1 is depicted which is rather similar to the tabletshown in FIG. 1A) with the difference that the lateral width a of thebasis area 22 of the front side 2 is larger than the transversal width bof the respective bulges 16, 20 of the front side 2 and the back side18, respectively. The embodiment of the tablet 1 of FIG. 2A) alsodiffers from that of FIG. 1A) insofar as the basis areas 22, 24 are nolonger completely flat as depicted in FIG. 1B) but can be curvedinwardly, in particular in a symmetrical manner towards the center, asdepicted in FIG. 2B).

Both embodiments as shown in FIGS. 1 and 2 have in common that thecircumferential rim 26 which connects the front side 2 and the back side18 has a rather flat profile as can be derived from FIGS. 1B) and 2B).

In FIG. 3A) another embodiment of tablet 1 of the invention is shownwhich differs from the tablet as depicted in FIG. 2A) insofar as thebasis areas 22 and 24 of the front side 2 and the back side 18,respectively, each are provided with four indentations 28. Theseindentations 28 have an essentially circular shape and are positioned ina row within the basis areas 22 and 24 (s.a. FIG. 3B) and FIG. 3C)). Ascan be derived from FIGS. 3B) and 3C) the indentations 28 of the frontside 2 are placed in a congruent manner with respect to the indentations30 in the basis area 24 of the back side 18. Again, the rim 26 has arather flat profile. The indentations 28, 30 have a trough-like, hollowform in the depicted embodiment, that is, from the circumferential rimof the indentations the depth is slightly increasing up to the center ofthe indentations, which can, for example be derived from FIG. 3B).

The embodiment of tablet 1 according to the invention as depicted inFIG. 4A) differs from the embodiment of FIG. 3A) in that the bulges 16and 20 of the front and back sides 2, 18 are no longer present along theentire circumference of the tablet. In the embodiment of FIG. 4 sectionsof the opposite transversal edges 12 and 14 of the front side 2 and backside 18 are no longer provided with a bulge section. Accordingly, thebulge 16 of the front side 2 extends only along the longitudinal edges 8and 10 of the front side as well as over portions of opposingtransversal edges 12 and 14 of the front side leaving on both opposingtransversal edges of the front and back side significant portionswithout any bulge. The same applies to the back side in the presentcase. The individual bulge portions of the front side of the embodimentof FIG. 4 have been assigned reference numbers 17 a and 17 b for thefront side 2 and 21 a and 21 b for the back side 18. The indentations 28and 30 of the front and back side are lying within the basis areas 22and 24, respectively, and are placed in a congruent manner as with theembodiment of FIG. 3 (s.a. FIG. 4C)). Again, the circumferential rim 26has an essentially flat configuration.

The embodiment of a tablet 1 of the present invention as depicted inFIG. 5A) differs from the tablet as shown in FIG. 4 only insofar as theindentations 28 of the front side 2 and the indentations 30 of the backside 18 are no longer located in a congruent manner, but are at leastpartially off-set as can be best derived from FIG. 5C).

FIG. 6A) shows another embodiment of a tablet 1 of the invention whichis rather similar to the embodiment depicted in FIG. 1, for example, asto the circumferential bulge 16 on the front side 2 as well as to thecircumferential bulge 20 on the back side 18 (not shown in FIG. 6A, butin FIGS. 6B) and 6C)) and as to its oblong shape and dimensions.Different from the tablet of FIG. 1 the embodiment shown in FIG. 6 makesuse of a circumferential land 32 on the front side 2 of a tablet as wellas of such a corresponding circumferential land 34 on back side 18 (notshown in FIG. 6A), but in FIGS. 6B) and 6C)). That is, thecircumferential bulges 16 and 20 are not extending up to circumferentialrim 26, but are located adjacent to, i.e. spaced apart from said rim 26.As can be derived from FIGS. 6B) and 6C) the bulge 16 does not smoothlygo over into the rim section 26, but terminates adjacent to the rimsection thereby furnishing a small portion which is located at a heightsomewhat similar to that of the basis area 22 of the front side 2. Thesame applies to the circumferential land 34 and the bulge 20 on the backside 18. In the embodiment shown in FIGS. 6A) to 6C) the land 32 of thefront side 2 is not exactly lying in the plane of the basis area 22, butslightly above. This can be best derived from FIG. 6C). The same appliesto the land 34 of the back side 18. For certain tablet formulations ithas been found advantageous to make use of, in particularcircumferential, land sections, for example, in order to alleviate thedie punching cycle in mass production.

A second aspect of the invention relates to a tamper-resistantpharmaceutical dosage form having a retarded release profile, especiallya tamper-resistant oral dosage form having a retarded release profile,particularly a tamper-resistant tablet having a retarded releaseprofile, comprising at least one pharmaceutically active ingredient withpotential for abuse, and having a shape comprising a longitudinal axisand two opposite longitudinal edges, a transversal axis perpendicular tothe longitudinal axis and two opposite transversal edges, a front side,an opposite back side and a circumferential rim between said front andback side, wherein the front side and/or the back side comprise a basisarea and wherein the front side and/or the back side comprise at leastone bulge which extends above said basis area, said at least one bulgebeing present at and/or adjacent to at least a section of one or bothlongitudinal edges and/or at and/or adjacent to at least a section ofone or both transversal edges and/or between both longitudinal edges andboth transversal edges. The front side and/or the back side of thedosage form, in particular the basis area of the front side and/or thebasis area of the back side, can further comprise at least oneindentation.

In general, the foregoing teachings relating to the first aspect of thepresent invention are also applicable to this second aspect of thepresent invention. However, there are emphasized the following:

A preferred embodiment of the tablet of the present invention is atablet with a length (longitudinal axis) of about 21 mm; a width(transversal axis) of about 9 mm; a thickness from the top of the bulgeon the front side to the top of the opposite bulge on the back side ofabout 5 mm; a thickness over the basis area of about 3 mm and anextension of the top of the bulge from the basis area of about 1 mm, andin particular having a circumferential bulge on the front and/or on theback side of the tablet, and preferably without any indentations, as forexample derivable from FIG. 1A.

Active ingredients with potential for abuse are known to the personskilled in the art and comprise tranquillisers, stimulants,barbiturates, narcotics, opioids or opioid derivatives.

A pharmaceutically active ingredient which is preferably used with thetamper-resistant tablets of the invention is an analgesic compound or apain-killing compound, such as for example an opioid or an opioidderivative, in particular tapentadol or salts thereof, more inparticular tapentadol.

By tamper-resistant it is meant that the active ingredient can notreadily be separated from the tablet in a form suitable for abusebecause the tablet is such that it can not easily be grinded. Thisrenders extraction of the active ingredient, which could be used fordrug-abuse, from the tablet difficult or this renders it very difficultto transform the tablet into a powder for sniffing.

The tablet of the invention can in one embodiment be renderedtamper-resistant by incorporating at least one synthetic or naturalpolymer which increases the breaking strength of the tablet so that itis much higher than a conventional tablet. In this way, pulverization ofthe tablet by conventional means, such as for example by a pestle andmortar, is rendered almost impossible, and, hence, the conversion of theactive ingredient incorporated in the tablet in a form which is suitablefor abuse is complicated.

In one embodiment of the present invention, said at least one syntheticor natural polymer is a polyalkylene oxide such as polyethylene oxideand polypropylene oxide and copolymers of ethylene oxide and propyleneoxide.

Preferably, the polyalkylene oxide is polyethylene oxide, in particularpolyethylene oxide having a molecular weight above 500,000, preferablyabove 1,000,000, and more preferably in the range of about 2,000,000 toabout 7,000,000. The amount of polyethylene oxide can in one embodimentrange from about 20 to about 80% (w/w), in particular from about 20 to50% (w/w), more in particular from about 30 to about 50% (w/w).

In one embodiment, the tablet of the present invention has a breakingstrength of at least 300 N, in particular at least 350N, more inparticular at least 400N, even more in particular at least 450 N. Thebreaking strength of the tablet of the invention can be determined bythe method for determining breaking strength of tablets described in theEuropean Pharmacopoeia 1997, page 143, 144, method No. 2.9.8.

Retarded release of an active ingredient from an oral dosage form isknown to a person skilled in the art. For a retarded release tablet, itusually is sufficient to administer the tablet once or twice daily. Theretarded release profile of the tablet of the present invention can beachieved by embedding the active ingredient in an amount of hydrophilicpolymer or of a blend of hydrophilic polymers, optionally alsocontaining conventional formulating agents. These hydrophilic polymerstend to swell upon contact with aqueous fluids following administration,and result in a viscous, drug release regulating gel layer. Preferablythe viscosity of these polymers ranges from 150 to 100.000 mPa·s(apparent viscosity of a 2% aqueous solution at 20° C.). Examples ofsuitable hydrophilic polymers include:

-   -   alkylcelluloses, such as, methylcellulose;    -   hydroxyalkylcelluloses, for example, hydroxymethylcellulose,        hydroxyethylcellulose, hydroxypropylcellulose and        hydroxybutylcellulose;    -   hydroxyalkyl alkylcelluloses, such as, hydroxyethyl        methylcellulose and hydroxypropyl methylcellulose;    -   carboxyalkylcelluloses, such as, carboxymethylcellulose;    -   alkali metal salts of carboxyalkylcelluloses, such as, sodium        carboxymethylcellulose;    -   carboxyalkylalkylcelluloses, such as,        carboxymethylethylcellulose;    -   carboxyalkylcellulose esters;    -   other natural, semi-synthetic, or synthetic polysaccharides,        such as, alginic acid, alkali metal and ammonium salts thereof,        carrageenans, galactomannans, tragacanth, agar-agar, gummi        arabicum, guar gummi, xanthan gummi, starches, pectins, such as        sodium carboxymethylamylopectin, chitin derivates such as        chitosan, polyfructans, inulin; polyacrylic acids and the salts        thereof;    -   polymethacrylic acids and the salts thereof, methacrylate        copolymers;    -   polyvinylalcohol;    -   polyvinylpyrrolidone, copolymers of polyvinylpyrrolidone with        vinyl acetate;    -   combinations of polyvinylalcohol and polyvinylpyrrolidone.

In one embodiment of the invention, the hydrophilic polymer in which theactive ingredient is embedded is selected from a cellulose derivative.Preferably, the cellulose derivative is a cellulose ether derivative,more preferably the cellulose ether derivative is HPMC. The amount ofcellulose derivative can in one embodiment range from about 1 to about20% (w/w), in particular from about 10 to about 20% (w/w).

In addition to said synthetic or natural polymer which increases thebreaking strength of the tablet, in particular polyalkylene oxide, andto said hydrophilic polymers, the tablet formulation in one embodimentcan further comprise a polyalkylene glycol, such as for example PEG6000. The amount of polyalkylene glycol can for example range from about1 to about 20% (w/w), in particular from about 1 to about 10% (w/w).

In one embodiment, the tamper-resistant tablet of the inventioncomprises at least one pharmaceutically active ingredient with potentialfor abuse, in particular a pain-killing drug, more in particular anopioid or an opioid derivative, e.g. tapentadol; at least onepolyalkylene oxide, in particular polyethylene oxide, more in particularpolyethylene oxide having a molecular weight in the range of about2,000,000 to 7,000,000; at least one cellulose ether derivative, inparticular hydroxypropyl methylcellulose (HMPC); and at least onepolyalkylene glycol, in particular polyethylene glycol, such as PEG6000. In preferred compositions further components can be present suchas anti-oxidants, for example vitamin E. In another embodiment, thetablet comprises pharmaceutically active ingredient with potential forabuse in an amount of at least 5 weight percent; polyethylene oxide inan amount of at least 15 weight percent; cellulose ether derivatives, inparticular HPMC, in an amount of at least 5 weight percent; andpolyalkylene glycol, in particular polyethylene glycol, in an amount ofat least 5 weight percent.

The tamper-resistant tablets of the present invention are preferablyprepared by melt-extruding the tablet formulation. The thus obtainedmelt-extruded strands are preferably cut into monoliths, which are thencompressed into tablets.

It has, for example, been found that in particular when the tablet ofthe invention is produced from melt extruded monolithic masses, veryhard compacted tablets are obtained which can no longer be easilygrinded or crushed thereby allowing for a very high degree oftamper-resistance. With these very hard tablets an improved control ofthe drug release profile can be obtained by the tablet of the presentinvention.

The tablets according to the invention are preferably prepared by way ofcompression using a die and a punch, preferably from a monolithic massobtained by melt extrusion. If obtained via melt extrusion, thecompressing step is preferably carried out with a monolithic massexhibiting ambient temperature, that is, a temperature in the range from20 to 25° C.

The strands obtained by way of extrusion can either be subjected to thecompression step as such or can be cut prior to the compression step. Itis of course also possible to subject the extruded strands to thecompression step or to the cutting step when still warm, that is more orless immediately after the extrusion step. The extrusion is preferablycarried out by way of twin-screw extruder.

The aforementioned polymers used for the preparation of the tablet ofthe invention, that is, the chains of these polymers are preferablypredominantly oriented along the direction of the extrusion. In case themonolith resulting from extrusion has a length greater than its width,the compression of said monolith is preferably performed with acompression direction perpendicular to the length.

A third aspect of the invention relates to a pharmaceutical dosage formwith controlled release of a pharmacologically active compound (A)contained therein, the pharmaceutical dosage form having a breakingstrength B₁ of at least 500 N in a direction of extension E₁, and havinga breaking strength B₂ of less than 500 N in a direction of extensionE₂.

In general, the foregoing teachings relating to the first aspect of theinvention and the second aspect of the invention are also applicable tothis third aspect of the invention. However, there are emphasized thefollowing:

Direction of extension E₁ and direction of extension E₂, respectively,can principally be any directions of extension of the pharmaceuticaldosage form, i.e., any arbitrarily chosen directions of extension,provided that the corresponding requirement for the breaking strength B₁and B₂, respectively, is satisfied.

The “breaking strength” (resistance to crushing) of a pharmaceuticaldosage form is known to the skilled person. In this regard it can bereferred to, e.g., W. A. Ritschel, Die Tablette, 2. Auflage, EditioCantor Verlag Aulendorf, 2002; H Liebermann et al., Pharmaceuticaldosage forms: Tablets, Vol. 2, Informa Healthcare; 2 edition, 1990; andEncyclopedia of Pharmaceutical Technology, Informa Healthcare; 1edition.

For the purpose of the specification, the breaking strength ispreferably defined as the amount of force that is necessary in order tofracture the pharmaceutical dosage form (=breaking force). Therefore,for the purpose of the specification the dosage form does preferably notexhibit the desired breaking strength when it breaks, i.e., is fracturedinto at least two independent parts that are separated from one another.In another preferred embodiment, however, the pharmaceutical dosage formis regarded as being broken if the force decreases by 25% (thresholdvalue) of the highest force measured during the measurement (see below).

The dosage forms according to the invention are preferably distinguishedfrom conventional dosage forms in that, due to their breaking strength,they cannot be pulverized by the application of force with conventionalmeans, such as for example a pestle and mortar, a hammer, a mallet orother usual means for pulverization, in particular devices developed forthis purpose (tablet crushers). In this regard “pulverization” meanscrumbling into small particles that would immediately release thepharmacologically active compound (A) in a suitable medium. Avoidance ofpulverization virtually rules out oral or parenteral, in particularintravenous or nasal abuse.

Conventional tablets typically have a breaking strength well below 200 Nin any direction of extension. The breaking strength of conventionalround tablets may be estimated according to the following empiricalformula: Breaking Strength [in N]=10× Diameter Of The Tablet [in mm].Thus, according to said empirical formula, a round tablet having abreaking strength of at least 500 N would require a diameter of at least50 mm (about 2 inches). Such a tablet, however, could not be swallowed.The above empirical formula does not apply to the pharmaceutical dosageforms of the invention, which are not conventional but rather special.

Further, the actual mean chewing force is about 220 N (cf., e.g., P. A.Proeschel et al., J Dent Res, 2002, 81(7), 464-468, copy attached). Thismeans that conventional tablets having a breaking strength well below200 N may be crushed upon chewing, whereas the dosage forms according tothe invention may not, at least not in direction of extension E₁.

Still further, when applying a gravitational acceleration of about 9.81m/s², 500 N correspond to a gravitational force of more than 50 kg, i.e.the pharmaceutical dosage forms according to the invention can withstanda weight of more than 50 kg, at least in direction of extension E₁.

Methods for measuring the breaking strength of a pharmaceutical dosageform are known to the skilled artisan. Suitable devices are commerciallyavailable.

For example, the breaking strength (resistance to crushing) can bemeasured in accordance with the European Pharmacopoeia 5.0, 2.9.8 or6.0, 2.09.08 “Resistance to Crushing of Tablets”. The test is intendedto determine, under defined conditions, the resistance to crushing oftablets, measured by the force needed to disrupt them by crushing. Theapparatus consists of 2 jaws facing each other, one of which movestowards the other. The flat surfaces of the jaws are perpendicular tothe direction of movement. The crushing surfaces of the jaws are flatand larger than the zone of contact with the tablet. The apparatus iscalibrated using a system with a precision of 1 Newton. The tablet isplaced between the jaws, taking into account, where applicable, theshape, the break-mark and the inscription; for each measurement thetablet is oriented in the same way with respect to the direction ofapplication of the force (and the direction of extension in which thebreaking strength is to be measured). The measurement is carried out on10 tablets, taking care that all fragments of tablets have been removedbefore each determination. The result is expressed as the mean, minimumand maximum values of the forces measured, all expressed in Newton.

A similar description of the breaking strength (breaking force) can befound in the US Pharmacopoeia. The breaking strength can alternativelybe measured in accordance with the method described therein where it isstated that the breaking strength is the force required to cause atablet to fail (i.e., break) in a specific plane. The tablets aregenerally placed between two platens, one of which moves to applysufficient force to the tablet to cause fracture. For conventional,round (circular cross-section) tablets, loading occurs across theirdiameter (sometimes referred to as diametral loading), and fractureoccurs in the plane. The breaking force of tablets is commonly calledhardness in the pharmaceutical literature; however, the use of this termis misleading. In material science, the term hardness refers to theresistance of a surface to penetration or indentation by a small probe.The term crushing strength is also frequently used to describe theresistance of tablets to the application of a compressive load. Althoughthis term describes the true nature of the test more accurately thandoes hardness, it implies that tablets are actually crushed during thetest, which is often not the case.

Alternatively, the breaking strength (resistance to crushing) can bemeasured in accordance with WO 2006/082099, which can be regarded as amodification of the method described in the European Pharmacopoeia. Theapparatus used for the measurement is preferably a “Zwick Z 2.5”materials tester, F_(max)=2.5 kN with a maximum draw of 1150 mm, whichshould be set up with one column and one spindle, a clearance behind of100 mm and a test speed adjustable between 0.1 and 800 mm/min togetherwith testControl software. Measurement is performed using a pressurepiston with screw-in inserts and a cylinder (diameter 10 mm), a forcetransducer, F_(max). 1 kN, diameter=8 mm, class 0.5 from 10 N, class 1from 2 N to ISO 7500-1, with manufacturer's test certificate M accordingto DIN 55350-18 (Zwick gross force F_(max)=1.45 kN) (all apparatus fromZwick GmbH & Co. KG, Ulm, Germany) with Order No BTC-FR 2.5 TH. D09 forthe tester, Order No BTC-LC 0050N. P01 for the force transducer, OrderNo BO 70000 S06 for the centring device.

In a preferred embodiment of the invention, the breaking strength ismeasured by means of a breaking strength tester Sotax®, type HT100(Allschwil, Switzerland). Preferably, the Auto Alignment™ device of theSotax® HT100 is not used, just to allow placing the dosage formindividually between the jaws in order to measure the breaking strengthin specific directions of extension. The Sotax® HT100 can measure thebreaking strength according to two different measurement principles:constant speed (where the test jaw is moved at a constant speedadjustable from 5-200 mm/min) or constant force (where the test jawincreases force linearly adjustable from 5-100 N/sec). In principle,both measurement principles are suitable for measuring the breakingstrength of the dosage form according to the invention. Preferably, thebreaking strength is measured at constant speed, preferably at aconstant speed of 120 mm/min.

In a preferred embodiment, the pharmaceutical dosage form is regarded asbeing broken if it is fractured into at least two separate pieces.

In another preferred embodiment, the pharmaceutical dosage form isregarded as being broken if the force decreases by 25% (threshold value)of the highest force measured during the measurement. For example, ifthe highest force measured during the measurement is 144 N, the tabletis regarded as being broken when the force decreases below 108 N (=75%of 144 N; decrease by 25%). The value of the breaking strength in therespective direction of extension is then 144 N. In a preferredembodiment, said threshold value is 30%, more preferably 35%, still morepreferably 40%, most preferably 45% and in particular 50%. Under thesecircumstances, a dosage form may have to be regarded as being brokenalthough it has not been fractured into at least two separate pieces.For example, a dosage form that has been torn in the middle but that hasnot been fragmented, may have to be regarded as being broken inaccordance with this definition of the breaking strength. Thus, inaccordance with this definition, failure of the breaking strength testat a particular force may be due to fracture of the dosage form or anyother deformation that causes the force to drop below the abovethreshold value, e.g. rupture, cracking, dunting, cleaving, fissure, andthe like.

FIG. 18 schematically illustrates the measurement of the breakingstrength of the dosage form depicted in FIG. 10, in particular theadjustment device for the dosage form used for this purpose before andduring the measurement, in three different directions of extension

a) to c). This measurement set-up is applicable to the various methodsfor measuring the breaking strength of the dosage form, including theabove method according to the European Pharmacopeia, the variationthereof (according to Zwick) and the preferred method using the Sotax®HT100. To this end, the dosage form is held between the plain jaw (61 a)and the plain jaw (61 b) of the force application apparatus (not shown)with the assistance of two 2-part clamping devices, which are in eachcase firmly attached (not shown) to the jaws once the spacing necessaryfor accommodating and centering the tablet to be measured has beenestablished. The spacing may be established by moving the 2-partclamping devices horizontally outwards or inwards in each case on thejaw on which they are mounted. The measurement of the breaking strengthin different directions of extensions is illustrated in FIG. 18A) toFIG. 18C). FIG. 18A) illustrates the arrangement for measuring thebreaking strength in direction of extension E₁ that is perpendicular tothe main direction of extension E₂ of the dosage form. FIG. 18B)illustrates the arrangement for measuring the breaking strength in themain direction of extension E₂ of the dosage form. This arrangement isthe standard arrangement when measuring the breaking strength ofconventional oblong tablets. The Auto Alignment™ device of the Sotax®HT100 serves the purpose of aligning the tablet shapes automatically inorder to ensure reproducible results in this direction of extension.According to the present invention, however, the breaking strength ofthe dosage form needs to be measured in different directions ofextension and the main direction of extension may be among saiddifferent directions of extension, but does not have to necessarily.FIG. 18C) illustrates the arrangement for measuring the breakingstrength in direction of extension E₃ that is perpendicular to the maindirection of extension E₂ of the dosage form as well as perpendicular todirection of extension E₁.

In a preferred embodiment, the breaking strength tester, preferably theSotax® HT100, is equipped with two plain jaws (cf. FIG. 18).

In another preferred embodiment, the breaking strength tester,preferably the Sotax® HT100, is equipped with two jaws that are notplain (cf. FIGS. 19, 20). Preferably, one jaw contains an embossment andthe other jaw contains an indentation. Embossment and indentation can becongruent with one another (like positive and negative), but do not haveto.

Preferably, the embossment serves as an arbor, spike or mandrel and canbe round of angular (e.g., triangular, rectangular, etc.). In apreferred embodiment, the embossment assumes the shape of a hemisphere.In another preferred embodiment, the embossment assumes the shape of acone. In yet another preferred embodiment, the embossment assumes theshape of a trigonal or rectangular pyramid. Most preferably, theembossment assumes the shape of a half cylinder, preferably having aradius of curvature of 2.5 mm. In a preferred embodiment, the centre ofsaid half cylinder lies within the surface of the main area of extensionof the jaw. In another preferred embodiment, the centre lies about 0.5mm away from said surface, just in the inside of the jaw.

Preferably, the indentation serves as a recess for the embossment. In apreferred embodiment, the indentation assumes the shape of a hollowhemisphere. In another preferred embodiment, the indentation assumes theshape of a hollow cone. In yet another preferred embodiment, theindentation assumes the shape of a hollow trigonal or rectangularpyramid. Most preferably, the indentation assumes the shape of achamfering, kerf or notch with an angle of preferably 90°.

FIG. 19A) shows a schematic view of jaw (61 a) containing embossment(62) and jaw (61 b) containing indentation (63/64). The embossment (62)assumes the shape of a half cylinder that is characterized by radius r.Preferably, r=2.5 mm. The center of the circular cross-section of thehalf cylinder may lie within the surface main area of extension of thejaw so that the entire half cylinder forms the embossment (62).Alternatively, the center of the circular cross-section of the halfcylinder may lie within the body of the jaw, e.g. at a distance r′ fromthe surface of the main area of extension, so that the only a part ofthe half cylinder forms the embossment (62). Preferably, r′=0 or 0.5 mm.The indentation is located in a rectangular recess (64) having a sidelength of 2 x₁+2 x₂ and a height of y₂. In the centre of saidrectangular recess (64) is located a chamfering, kerf or notch (63)having a side length of 2 x₁ and a height/depth of y₁. In a preferredembodiment, x₁=3 mm, x₂=6 mm, y₁=3 mm and y₂=2 mm. In another preferredembodiment, x₁=4 mm, x₂=7 mm, y₁=4 mm and y₂=2 mm. Preferably, thechamfering, kerf or notch (63) assumes an angle of 90°. FIG. 19B) showsa schematic view of jaws (61 a) and (61 b) on faces (65 a) and (65 b),respectively.

FIG. 20 shows in analogy to FIG. 18 how the dosage form depicted in FIG.10 should be placed between the two jaws having embossment andindentation, respectively, in order to measure the breaking strength indirections of extension E₁, E₂ and E₃. The skilled person recognizesthat during the measurement, i.e. the movement of the jaws towards oneanother, it may become necessary to additionally clamp the dosage form,e.g. by means of suitable guiding shafts or leading tracks (not shown),in order to avoid that the dosage form is tilted or evades to the side.

In general, a measuring set-up with jaws equipped with embossment andindentation (cf. FIG. 20) realizes harsher measuring conditions than ameasuring set-up with plain jaws (cf. FIG. 18). Thus, it may happen thata given dosage form which passes the measurement in accordance with FIG.18 fails when being measured in the same direction of extension inaccordance with FIG. 20.

As far as tablet orientation during the measurement of the breakingforce is concerned, the US Pharmacopoeia (USP) states that in general,tablets are tested either across the diameter or parallel to the longestaxis. Scored tablets have two orientation possibilities. When they areoriented with their scores perpendicular to the platen faces, thelikelihood that tensile failure will occur along the scored lineincreases. This provides information about the strength of the matrix atthe weakest point in the structure. When scored tablets are orientedwith their scores parallel to the platen faces, more general informationabout the strength of the matrix is derived. Capsule-shaped tablets orscored tablets may best be broken in a three-point flexure test. Afitting, which is either installed on the platens or substituted for theplatens, supports the tablet at its ends and permits the breaking loadto be applied to the opposite face at the unsupported midpoint of thetablet. The fittings are often available from the same source thatsupplies the hardness tester. FIG. 20 is in accordance with thisdescription in the USP.

The pharmaceutical dosage form according to the invention preferably hasa breaking strength B₁ of at least 500 N in direction of extension E₁.Preferably, direction of extension E₁ is perpendicular to the maindirection of extension of the dosage form. Preferably, the breakingstrength in direction of extension E₁ is at least 500 N regardless ofwhether the measuring device is equipped with plain jaws or with twojaws one of which containing an embossment and the other containing anindentation, as described above.

Further, the pharmaceutical dosage form according to the inventionpreferably has a breaking strength B₂ of less than 500 N in direction ofextension E₂. Preferably, direction of extension E₂ is the maindirection of extension of the dosage form. Preferably, the breakingstrength in direction of extension E₂ is less than 500 N when beingmeasured with two plain jaws. However, it is not required (but possible)that the breaking strength in direction of extension E₂ is less than 500N when being measured with two jaws one of which containing anembossment and the other containing an indentation, as described above.

In a preferred embodiment according to the invention, the breakingstrength B₁ of the pharmaceutical dosage form in direction of extensionE₁ is measured in accordance with FIG. 20A), i.e. orthogonal to the maindirection of extension and by means of embossment and indentation. Thebreaking strength B₂ in direction of extension E₂, however, ispreferably measured in accordance with FIG. 18B), i.e. along the maindirection of extension and by means of plain jaws.

The pharmaceutical dosage form according to the invention preferablyexhibits mechanical strength over a wide temperature range, in additionto the breaking strength (resistance to crushing) optionally alsosufficient hardness, impact resistance, impact elasticity, tensilestrength and/or modulus of elasticity, optionally also at lowtemperatures (e.g. below −24° C., below −40° C. or in liquid nitrogen),for it to be virtually impossible to pulverize by spontaneous chewing,grinding in a mortar, pounding, etc. Thus, preferably, in direction ofextension E₁ the comparatively high breaking strength of thepharmaceutical dosage form according to the invention is maintained evenat low or very low temperatures, e.g., when the pharmaceutical dosageform is initially chilled to increase its brittleness, for example totemperatures below −25° C., below −40° C. or even in liquid nitrogen.

The pharmaceutical dosage form according to the invention is preferablycharacterized by a certain degree of breaking strength. This does notmean that the pharmaceutical dosage form must also exhibit a certaindegree of hardness. Hardness and breaking strength are differentphysical properties. Therefore, the tamper resistance of thepharmaceutical dosage form does not necessarily depend on the hardnessof the pharmaceutical dosage form. For instance, due to its breakingstrength, impact strength, elasticity modulus and tensile strength,respectively, the pharmaceutical dosage form can preferably be deformedwhen exerting an external force, for example using a hammer, but cannotbe pulverized, i.e., crumbled into a high number of fragments. In otherwords, the pharmaceutical dosage form according to the invention ischaracterized by a certain degree of breaking strength, but notnecessarily also by a certain degree of form stability.

Therefore, in the meaning of the specification, a pharmaceutical dosageform that is deformed when being exposed to a force in a particulardirection of extension but that does not break is to be regarded ashaving the desired breaking strength in said direction of extension.

Due to the anisotropic mechanical properties in directions of extensionE₁ and E₂, the application of force with conventional means, e.g. theapplication of 400 N, may cause disruption of the dosage form to acertain and limited degree, but may not cause pulverization thereof. Forexample, when the breaking strength in direction of extension E₂ isbelow 400 N, the dosage form is disrupted into pieces by applying 400 Nin direction of extension E₂. Preferably, however, said pieces may notbe disrupted any further by applying 400 N or more.

It has been surprisingly found that the outer shape of thepharmaceutical dosage forms may be varied within wide limits withoutdiminishing their breaking strength. Although a variation of the outershape of the pharmaceutical dosage forms may cause a decrease of thebreaking strength in a certain direction of extension, it has been foundthat specific forms and shapes establish a certain degree of fragilityat predetermined sites of fracture (weakening points) without completelydiminishing the overall breaking strength of the remainder of thepharmaceutical dosage forms (fragments).

The degree of weakening can be controlled and when exerting a force onthe pharmaceutical dosage forms, said weakening points can serve aspredetermined sites of fracture, provided that the amount of force issufficiently high.

The degree of fragility may be adjusted to values that are still wellabove the typical breaking strength of conventional pharmaceuticaldosage forms, e.g. well above 100 N or 200 N. In particular, it has beensurprisingly found that pharmaceutical dosage forms can be designedwhich can be fractured into large pieces, e.g. into halves or thirds, byconventional means (e.g. tablet crushers), but not any further. Inconsequence, the resultant fragments (subunits) in turn exhibit abreaking strength which is far above the breaking strength at thepredetermined site of fracture, e.g. well above 500 N, preferably in anydirection of extension.

FIG. 7A) is a schematic view of a conventional oblong tablet.Cross-sectional areas (35) and (35′) are smaller than cross-sectionalareas (36) and (36′) which in turn are smaller than cross-sectional area(37). When exerting external force (F₂) in direction of extension (E₂),the implied pressure is not constant but varies with varyingcross-sectional areas. For example, the pressure implied at the sectionhaving cross-sectional area (37) is lower than the pressure at thesection having cross-sectional areas (35) and (35′), respectively,because cross-sectional area (37) is larger than cross-sectional areas(35) and (35′).

FIG. 7B) is a schematic view of an embodiment of a pharmaceutical dosageform according to the invention. An increased surface to volume ratioand surface to weight ratio, respectively, is achieved by taper T rightin the middle of the pharmaceutical dosage form. Under thesecircumstances, when exerting external force (F₂) in direction ofextension (E₂), the implied pressure at the section havingcross-sectional area (42) is higher than the pressure at the sectionhaving cross-sectional areas (38) and (38′), respectively, becausecross-sectional area (42) is smaller than cross-sectional areas (38) and(38′). The pharmaceutical dosage form depicted in FIG. 7B) exhibits abreaking strength in direction of extension (E₂) that is substantiallylower than the breaking strength of the pharmaceutical dosage formdepicted in FIG. 7A) in direction of extension (E₂).

In FIGS. 7A) and 7B), direction of extension (E₂) is the principaldirection of extension of the pharmaceutical dosage forms (maindirection of extension, major direction of extension).

The predetermined sites of fracture (weakening points) can improve thepatient compliance, as patients having problems in swallowing largepharmaceutical dosage forms can fracture the pharmaceutical dosage formsalong the predetermined sites of fracture (weakening points) prior toswallowing. Those patients can limitedly fracture the pharmaceuticaldosage form into fragments of a size they can swallow. However, as theresultant fragments in turn cannot be comminuted any further, at leastnot by conventional means, the pharmaceutical dosage forms are stilltamper resistant, i.e. efficiently avoid drug abuse and (unintentional)drug overdose, respectively. In other words, the pharmaceutical dosageforms according to the invention realize both, a very high mechanicalresistance in order to avoid misuse as well as a certain degree of amechanical weakness in order to improve patient compliance.

In a preferred embodiment, the pharmaceutical dosage form according tothe invention provides fragments when exerting a force higher than B₂ indirection of extension E₂, preferably under the standard conditions formeasuring the breaking strength set forth above, said fragments in turnhaving a breaking strength of preferably at least 500 N, at least 550 Nor at least 600 N; more preferably at least 650 N, at least 700 N or atleast 750 N; still more preferably at least 800 N, at least 850 N or atleast 900 N; yet more preferably at least 950 N, at least 1000 N or atleast 1100 N; and in particular at least 1200 N, at least 1300 N, atleast 1400 N or at least 1500 N; preferably in any (each and every) oftheir directions of extension.

Preferably, the dosage form provides at most 10, more preferably at most8, still more preferably at most 6, yet more preferably at most 5, mostpreferably at most 4 and in particular at most 3 fragments when exertinga force that is higher than B₂ in direction of extension E₂.

Preferably the volume of each fragment is at least 5%, more preferablyat least 10%, still more preferably at least 15%, yet more preferably atleast 20%, most preferably at least 25% and in particular at least 30%of the volume of the pharmaceutical dosage form.

It has been surprisingly found that the release profile of thepharmaceutical dosage form may be varied within certain limits byvarying the outer shape of the pharmaceutical dosage form withoutdiminishing its tamper resistance. Therefore, particularly at a highdrug load, the pharmaceutical dosage forms according to the inventionallow to realize release profiles that may not be achieved withconventional pharmaceutical dosage forms having an increased breakingstrength (e.g. oblong tablets).

Typically, the pharmaceutical dosage form according to the inventionassumes the form of a tablet. The pharmaceutical dosage form ispreferably not in film form.

The pharmaceutical dosage form according to the invention may assumevarious shapes. Preferably, from top view, the shape of thepharmaceutical dosage form can be substantially hexagonal, elliptic,cyclic, oblong, rectangular, squared, triangular, and the like.Preferably, from side view, the shape of the pharmaceutical dosage formcan be substantially flat-convex, biconvex, flat with facet, flatwithout facet, cyclic, and the like.

For example, the pharmaceutical dosage form according to the inventionmay assume simple geometries, such as spherical, planar, cubic,hexagonal and cylindrical, or complex geometries, such as convex, hollowcylindrical, doughnut-shaped, hemispheric, cruciform, astral (cf. FIGS.13, 14 and 15).

Particularly preferred shapes of the dosage form according to theinvention have already been described in connection with the first andsecond aspects of the invention above.

In a particularly preferred embodiment, the pharmaceutical dosage formaccording to the invention can be described as a body having a recess orcavity on at least one side, preferably two recesses or two cavities ontwo sides, preferably on opposing sides. Alternatively, said cavitiesand recesses, respectively, may be regarded as bulges, indentations,troughs, hollows, depressions, synclines, deepenings, and the like.Examples of such embodiments are depicted in FIGS. 8-10, 16A) and 16B).

The pharmaceutical dosage form is preferably adapted for oraladministration, i.e., should be capable of being swallowed. Thus,obscure geometrical forms which are obviously harmful cannot be regardedas pharmaceutical dosage forms according to the invention.

According to a preferred embodiment, the pharmaceutical dosage form ischaracterized by a specific aspect ratio. For the purpose of thespecification, the aspect ratio is defined as the ratio of the maindirection of extension of the dosage form to the maximum extension ofthe pharmaceutical dosage form orthogonal to said main direction ofextension, e.g. maximum length to maximum height (and maximum length tomaximum width, respectively). Preferably, said aspect ratio is withinthe range of 2.4±1.3:1, more preferably 2.4±1.0:1, still more preferably2.4±0.8:1, yet more preferably 2.4±0.6:1, most preferably 2.4±0.4:1 andin particular 2.4±0.2:1.

According to a preferred embodiment, the pharmaceutical dosage form ischaracterized by a specific length to height to width ratio, wherelength>height≧width. For the purpose of the specification, in thisembodiment the length corresponds to the main direction of extension ofthe dosage form, the height corresponds to the maximum extension of thepharmaceutical dosage form orthogonal to the length, and the widthcorresponds to the maximum extension orthogonal to the length andorthogonal to the width (Cartesian space). Preferably, the length toheight to width ratio is within the range of 4.7±2.0:2.0±1.0:1, morepreferably 4.7±1.6:2.0±0.8:1, still more preferably 4.7±1.2:2.0±0.6:1,yet more preferably 4.7±0.8:2.0±0.4:1, most preferably4.7±0.6:2.0±0.3:1, and in particular 4.7±0.4:2.0±0.2:1.

Preferably, a portion of the surface of the pharmaceutical dosage formis convex, i.e. curved out or bulged outward, and another portion of itssurface is concave, i.e. curved in or hollowed inward. For the purposeof the specification, the radius of curvature is not critical.

Preferably, the overall surface of the pharmaceutical dosage form can bedivided into concave portions, convex portions and planar portions.Typically, the sum of the concave portions, convex portions and planarportions corresponds to the overall surface of the dosage form. However,at least theoretically, a given portion can be convex and concavesimultaneously (saddle). Under these circumstances, the sum of theconcave portions, convex portions and planar portions exceeds theoverall surface of the dosage form.

In a preferred embodiment, the convex portion of the surface of thedosage form is at most 95%, more preferably at most 90% or at most 85%,still more preferably at most 80% or at most 75%, yet more preferably atmost 70% or at most 65%, most preferably at most 60% or at most 55% andon particular at most 50% or at most 45%, based on the sum of concaveportions, convex portions and planar portions.

In another preferred embodiment, the concave portion of the surface ofthe dosage form is at least 5%, more preferably at least 10% or at least15%, still more preferably at least 20% or at least 25%, yet morepreferably at least 30% or at least 35%, most preferably at least 40% orat least 45% and in particular at least 50% or at least 55%, based onthe sum of concave portions, convex portions and planar portions.

In a preferred embodiment of the pharmaceutical dosage form according tothe invention, the maximum extension of the dosage form orthogonal tothe main area of extension of the dosage form is spaced from the centreof mass of the dosage form parallel to said main area of extension. Forthe purpose of the specification, the main area of extension of thedosage form is preferably the largest plain area that can be placedalong a cut of the body of the dosage form. This embodiment is furtherillustrated in FIG. 17A) which shows a schematic view of thecross-sectional face of the preferred pharmaceutical dosage formdepicted in FIG. 10. The maximum extension (56) of the dosage formorthogonal to the main area of extension (57) of the dosage form isspaced from the centre of mass (58) of the dosage form parallel to saidmain area of extension (57).

Preferably, the closest distance (59) from the maximum extension of thedosage form orthogonal to the main area of extension of the dosage formto the centre of mass of the dosage form is at least 0.5 mm, morepreferably at least 1.0 mm, still more preferably at least 1.5 mm, yetmore preferably at least 2.0 mm, most preferably at least 2.5 mm and inparticular at least 3.0 mm.

Preferably, the pharmaceutical dosage form according to the inventionhas a shape so that when exerting an increasing amount of force indirection of extension E₂, the dosage form is firstly deformed and, whenthe amount of force reaches the breaking strength B₂, deformation causestractive forces that lead to disruption of the dosage form.

In a preferred embodiment, the cross sectional area of thepharmaceutical dosage form that is orthogonal to the main direction ofextension and that contains the centre of mass of the dosage form has ashape so that at least 50%, more preferably at least 60% and inparticular at least 75% of its area is spaced at least 0.2 mm, at least0.3 mm, at least 0.4 mm or at least 0.5 mm, more preferably at least 0.6mm, at least 0.7 mm, at least 0.8 mm or at least 0.9 mm, still morepreferably at least 1.0 mm, at least 1.1 mm, at least 1.2 mm or at least1.3 mm, yet more preferably at least 1.4 mm, at least 1.5 mm, at least1.6 mm or at least 1.7 mm, most preferably at least 1.8 mm, at least 1.9mm, at least 2.0 mm or at least 2.1 mm and in particular at least 2.2mm, at least 2.3 mm, at least 2.4 mm or at least 2.5 mm from the centreof mass. Preferably, said cross sectional area contains the centre ofmass as well as direction of extension E₁, or the centre of mass as wellas direction of extension E₂. This embodiment is further illustrated inFIG. 17B) in which the centre of mass (58) is surrounded by concentricrings (60 a) to (60 d) indicating increasing distances from the centreof mass (58). The portions of the cross sectional area which do notoverlap with any of the concentric rings are spaced from the centre ofmass by more than the radius of ring (60 d).

In a preferred embodiment of the pharmaceutical dosage form according tothe invention, the closest distance of each and every geometrical pointwithin the dosage form to the surface of the dosage form is at most 10mm, at most 9 mm, at most 8 mm or at most 7.5 mm; more preferably atmost 7.0 mm, at most 6.5 mm or at most 6.0 mm; still more preferably atmost 5.8 mm, at most 5.6 mm, at most 5.4 mm, at most 5.2 mm or at most5.0 mm; yet more preferably at most 4.8 mm, at most 4.6 mm, at most 4.4mm, at most 4.2 mm or at most 4.0 mm; yet more preferably at most 3.8mm, at most 3.6 mm, at most 3.4 mm, at most 3.2 mm or at most 3.0 mm;most preferably at most 2.8 mm, at most 2.6 mm, at most 2.4 mm, at most2.2 mm or at most 2.0 mm; and in particular at most 1.8 mm, at most 1.6mm, at most 1.4 mm, at most 1.2 mm or at most 1.0 mm.

Preferably, the pharmaceutical dosage form according to the invention isnot radial symmetric about its main direction of extension (principaldirection of extension), preferably the pharmaceutical dosage form isnot radial symmetric at all.

In a preferred embodiment, the symmetry of the pharmaceutical dosageform is selected from the group consisting of C_(i), C_(s), C₁, C₂, C₃,C₄, C₅, C₆, C₇, C₈, C_(∞), C_(2h), C_(3h), C_(4h), C_(5h), C_(6h),C_(7h), C_(8h), C_(∞h), C_(2v), C_(3v), C_(4v), C_(5v), C_(6v), C_(7v),C_(8v), C_(∞v), C_(3i), D₂, D₃, D₄, D₅, D₆, D₇, D₈, D_(∞), D_(2h),D_(3h), D_(4h), D_(5h), D_(6h), D_(7h), D_(8h), D_(∞h), D_(2d), D_(3d),D_(4d), D_(5d), D_(6d), D_(7d), D_(8d), D_(∞d), S₂, S₄, S₆, S₈, T,T_(h), T_(d), O, O_(h) and I_(h) according to Schoenflies notation.D_(2h) and D_(4h) are particularly preferred.

In a preferred embodiment, the centre of mass of the pharmaceuticaldosage form lies within the main area of extension of the dosage form.Preferably, the pharmaceutical dosage form is symmetric about its mainarea of extension.

The pharmaceutical dosage form according to the invention preferably hasa breaking strength B₁ of at least 500 N in at least one of itsdirections of extension, namely E₁, preferably, however, in more thanone of its directions of extension, more preferably in a plurality ofdirections of extension.

In direction of extension E₁ the pharmaceutical dosage form according tothe invention preferably has a breaking strength B₁ of at least 500 N,preferably of at least 510 N, at least 520 N, at least 530 N, at least540 N or at least 550 N; more preferably at least 560 N, at least 570 N,at least 580 N, at least 590 N or at least 600 N; still more preferablyat least 620 N, at least 640 N, at least 660 N, at least 680 N or atleast 700 N; yet more preferably at least 720 N, at least 740 N, atleast 760 N, at least 780 N or at least 800 N; most preferably at least850 N, at least 900 N, at least 950 N, at least 1000 N or at least 1050N; and in particular at least 1100 N, at least 1200 N, at least 1300 N,at least 1400 N, at least 1500 N, at least 1600 N, at least 1700 N, atleast 1800 N, at least 1900 N or at least 2000 N.

E₁ may be any direction of extension of the pharmaceutical dosage form,i.e. any straight line connecting any first point on the surface of thepharmaceutical dosage form with any second point on the surface of thepharmaceutical dosage form. Preferably, said straight line liescompletely within the body of the pharmaceutical dosage form, i.e.,preferably does not “leave” the pharmaceutical dosage form somewhere and“reenters” the pharmaceutical dosage form elsewhere. Preferably, thedistance between said first point and said second point of direction ofextension E₁ is at least 50%, more preferably at least 75% of the maindirection of extension of the pharmaceutical dosage form. The latter isdefined as the maximal distance between two points on the surface of thepharmaceutical dosage form (principal direction of extension),regardless of whether it completely lies within the body of the dosageform or not. Preferably, the main direction of extension of the dosageform goes through the centre of mass of the dosage form.

In a preferred embodiment, the main direction of extension of thepharmaceutical dosage form according to the invention is not longer than32 mm, more preferably not longer than 30 mm, still more preferably notlonger than 28 mm, yet more preferably not longer than 26 mm, mostpreferably not longer than 24 mm, and in particular not longer than 22mm.

In a preferred embodiment, the pharmaceutical dosage form according tothe invention is deformed in the breaking strength tester when themeasurement of the breaking strength is conducted. Deformation meanstypically compression, although bending, turning and other modes ofdeformation are also possible. When exerting a force of 100 N indirection of extension E₁, the dosage form is preferably deformed by atleast 0.1 mm but does not break. When exerting a force of 200 N indirection of extension E₁, the dosage form is preferably deformed by atleast 0.2 mm, more preferably at least 0.3 mm, but does not break. Whenexerting a force of 300 N in direction of extension E₁, the dosage formis preferably deformed by at least 0.5 mm, more preferably at least 0.7mm, but does not break. When exerting a force of 400 N in direction ofextension E₁, the dosage form is preferably deformed by at least 1.0 mm,more preferably at least 1.2 mm, but does not break. When exerting aforce of 500 N in direction of extension E₁, the dosage form ispreferably deformed by at least 1.5 mm, more preferably at least 2.0 mm,but does not break. When exerting a force of 1000 N in direction ofextension E₁, the dosage form is preferably deformed by at least 3.0 mm,more preferably at least 4.0 mm, but does not break.

For theoretical reasons, every pharmaceutical dosage form comprises anunlimited number of directions of extension.

Some typical directions of extension of a preferred pharmaceuticaldosage form according to the invention are illustrated in FIG. 8. FIG.8A) shows different directions of extension. Directions of extension E₉and E₁₀ are parallel to one another, directions of extension E₁₀, E₁₁and E₁₂ (and E₉, respectively) are orthogonal to one another. Directionsof extension E₉, E₁₀, E₁₁ and E₁₂ enter the body of the pharmaceuticaldosage form at sites (43), (44), (45) and (46), respectively. Directionof extension E₉ lies completely within the body of the pharmaceuticaldosage form; it enters the body of the pharmaceutical dosage form atsite (43 and leaves the body of the pharmaceutical dosage form at itsrear side (not shown). Direction of extension E₁₀, however, enters thebody of the pharmaceutical dosage form at site (44), transiently leavesthe body of the pharmaceutical dosage form at the rear side of the upperfront edge (not shown) and re-enters the body of the pharmaceuticaldosage form at site (44′), before it finally leaves the body of thepharmaceutical dosage form at its rear side (not shown). Direction ofextension E₁₃ enters the body of the pharmaceutical dosage form atcorner (47) and leaves the pharmaceutical dosage form at the diagonallyopposite corner. The dotted line of direction of extension E₁₃represents the maximal distance between two points on the surface of thepharmaceutical dosage form, i.e., direction of extension E₁₃ is the maindirection of extension of the pharmaceutical dosage form. In total, thepharmaceutical dosage form depicted in FIG. 8A) has four of such maindirections of extension.

FIG. 8B) shows a cross-sectional view of the pharmaceutical dosage formaccording to FIG. 8A). The cross-sectional face (48, hatched) assumesthe shape of an H. The pharmaceutical dosage form assumes a rectangularshape with two recesses (50, 50′) on opposing sides. In other words, thepharmaceutical dosage form has the size of a comparatively flatrectangle with an edge (49) circumventing the upper side and an edge(49′) circumventing the opposite side. Pharmaceutical dosage forms ofthis type may be manufactured by a tabletting tool that is equipped witha so-called H-plunger.

FIG. 9A) is a schematic view of the cross-sectional face (48) of thepharmaceutical dosage form depicted in FIG. 8A). FIG. 9B) is a schematicview of the cross-sectional face of a pharmaceutical dosage formaccording to the invention that is similar to the cross-sectional faceof the pharmaceutical dosage form depicted in FIG. 9A). The rim (49) ofthe cross-sectional face, however, is rounded (51) thereby forming aconvex surface area. FIG. 9C is a schematic view of the cross-sectionalface of a pharmaceutical dosage form according to the invention that issimilar to the cross-sectional face of pharmaceutical dosage formsdepicted in FIGS. 9A) and 9B). The edge at the bottom of the recess isrounded (52) thereby forming a concave surface area.

FIG. 10 is a schematic view of a particularly preferred pharmaceuticaldosage form according to the invention. FIG. 10A) is a top view which isidentical from both opposing sides and FIG. 10B) is a side-view which isalso identical from both opposing sides.

In the Cartesian space, the principal dimensions of the pharmaceuticaldosage form schematically illustrated in FIG. 10 can be defined as a, band c, where a=a₁+a₂+a₃, b=b₁+b₂+b₃ and c=c₁+c₂+c₃. Preferred relativedimensions D1 to D6 of the pharmaceutical dosage form depicted in FIG.10 can be defined in relative relations of a, b and c; a₁, a₂ and a₃;b₁, b₂ and b₃; and c₁, c₂ and c₃, respectively:

D1: c>a≧b; c>a>b;

D2: c>1.5 a; c>2 a; c>2.5 a; c>3 a;

D3: a₂>a₁≈a₃; a₂>1.1 a₁≈1.1 a₃; a₂>1.2 a₁≈1.2 a₃; a₂>1.3 a₁≈1.3 a₃;

D4: b₂≧b₁≈b₃; b₂≦1.1 b₃; b₂≧1.2 b₂≧1.2 b₃; b₂≧1.3 b₁≈1.3 b₃;

D5: b₂≦b₁≈b₃; b₂≦0.9 b₁≈0.9 b₃; b₂≦0.8 b₁≈0.8 b₃; b₂≦0.7 b₁≈0.7 b₃;and/or

D6: c₂>c₁≈c₃; c₂>1.1 c₁≈1.1 c₃; c₂≈1.2 c₁≈1.2 c₃; c₂>1.3 c₁≈1.3 c₃.

Preferred embodiments D7 to D18 regarding the absolute dimensions of thepharmaceutical dosage form depicted in FIG. 10 are displayed in thetable here below:

[mm] D7 D8 D9 D10 D11 D12 a 8.6 ± 4.3 8.6 ± 2.1 8.6 ± 1.0 9.0 ± 4.5 9.0± 2.2 9.0 ± 1.1 b 4.9 ± 2.5 4.9 ± 1.3 4.9 ± 0.7 4.3 ± 2.1 4.3 ± 1.0 4.3± 0.6 c 21.9 ± 11.0 21.9 ± 5.5  21.9 ± 2.7  20.4 ± 10.2 20.4 ± 5.1  20.4± 2.5  [mm] D13 D14 D15 D16 D17 D18 a 9.0 ± 4.3 9.0 ± 2.1 9.0 ± 1.0 9.1± 4.5 9.1 ± 2.2 9.1 ± 1.1 b 4.1 ± 2.5 4.1 ± 1.3 4.1 ± 0.7 4.5 ± 2.1 4.5± 1.0 4.5 ± 0.6 c 20.5 ± 11.0 20.5 ± 5.5  20.5 ± 2.7  20.5 ± 10.2 20.5 ±5.1  20.5 ± 2.5 

Preferred embodiments D19 to D30 regarding the absolute dimensions ofthe pharmaceutical dosage form depicted in FIG. 10 are displayed in thetable here below:

[mm] D19 D20 D21 D22 D23 D24 a 8.6 ± 4.3 8.6 ± 2.1 8.6 ± 1.0 9.0 ± 4.59.0 ± 2.2 9.0 ± 1.1 a₁ 3.3 ± 1.6 3.3 ± 0.8 3.3 ± 0.4 3.5 ± 1.8 3.5 ± 0.93.5 ± 0.5 a₂ 2.1 ± 1.0 2.1 ± 0.5 2.1 ± 0.3 2.1 ± 1.1 2.1 ± 0.6 2.1 ± 0.3a₃ 3.3 ± 1.6 3.3 ± 0.8 3.3 ± 0.4 3.5 ± 1.8 3.5 ± 0.9 3.5 ± 0.5 b 4.9 ±2.5 4.9 ± 1.3 4.9 ± 0.7 4.3 ± 2.1 4.3 ± 1.0 4.3 ± 0.6 b₁ 0.9 ± 0.5 0.9 ±0.3 0.9 ± 0.2 0.9 ± 0.4 0.9 ± 0.2 0.9 ± 0.1 b₂ 3.1 ± 1.5 3.1 ± 0.7 3.1 ±0.4 2.6 ± 1.3 2.6 ± 0.6 2.6 ± 0.3 b₃ 0.9 ± 0.5 0.9 ± 0.3 0.9 ± 0.2 0.9 ±0.4 0.9 ± 0.2 0.9 ± 0.1 c 21.9 ± 11.0 21.9 ± 5.5  21.9 ± 2.7  20.4 ±10.2 20.4 ± 5.1  20.4 ± 2.5  c₁ 3.2 ± 1.6 3.2 ± 0.8 3.2 ± 0.4 3.3 ± 1.73.3 ± 0.9 3.3 ± 0.4 c₂ 15.6 ± 7.8  15.6 ± 3.9  15.6 ± 2.0  13.8 ± 6.9 13.8 ± 3.5  13.8 ± 1.7  c₃ 3.2 ± 1.6 3.2 ± 0.8 3.2 ± 0.4 3.3 ± 1.7 3.3 ±0.9 3.3 ± 0.4 D25 D26 D27 D28 D29 D30 a 9.0 ± 4.3 9.0 ± 2.1 9.0 ± 1.09.1 ± 4.5 9.1 ± 2.2 9.1 ± 1.1 a₁ 3.2 ± 1.6 3.2 ± 0.8 3.2 ± 0.4 3.2 ± 1.83.2 ± 0.9 3.2 ± 0.5 a₂ 2.6 ± 1.0 2.6 ± 0.5 2.6 ± 0.3 2.7 ± 1.1 2.7 ± 0.62.7 ± 0.3 a₃ 3.2 ± 1.6 3.2 ± 0.8 3.2 ± 0.4 3.2 ± 1.8 3.2 ± 0.9 3.2 ± 0.5b 4.1 ± 2.5 4.1 ± 1.3 4.1 ± 0.7 4.5 ± 2.1 4.5 ± 1.0 4.5 ± 0.6 b₁ 1.0 ±0.5 1.0 ± 0.3 1.0 ± 0.2 1.0 ± 0.4 1.0 ± 0.2 1.0 ± 0.1 b₂ 2.1 ± 1.5 2.1 ±0.7 2.1 ± 0.4 2.5 ± 1.3 2.5 ± 0.6 2.5 ± 0.3 b₃ 1.0 ± 0.5 1.0 ± 0.3 1.0 ±0.2 1.0 ± 0.4 1.0 ± 0.2 1.0 ± 0.1 c 20.5 ± 11.0 20.5 ± 5.5  20.5 ± 2.7 20.5 ± 10.2 20.5 ± 5.1  20.5 ± 2.5  c₁ 3.3 ± 1.6 3.3 ± 0.8 3.3 ± 0.4 3.3± 1.7 3.3 ± 0.9 3.3 ± 0.4 c₂ 13.9 ± 7.8  13.9 ± 3.9  13.9 ± 2.0  13.9 ±6.9  13.9 ± 3.5  13.9 ± 1.7  c₃ 3.3 ± 1.6 3.3 ± 0.8 3.3 ± 0.4 3.3 ± 1.73.3 ± 0.9 3.3 ± 0.4

The pharmaceutical dosage form according to the invention preferably hasa breaking strength B₂ in a second direction of extension E₂, whereinB₂<500 N.

Direction of extension E₁ differs from direction of extension E₂. E₂ maybe any direction of extension of the pharmaceutical dosage form, i.e.any straight line connecting any first point on the surface of thepharmaceutical dosage form with any second point on the surface of thepharmaceutical dosage form. Preferably, said straight line liescompletely within the body of the pharmaceutical dosage form, i.e.,preferably does not “leave” the pharmaceutical dosage form somewhere and“re-enters” the pharmaceutical dosage form elsewhere. Preferably, thedistance between said first point and said second point is at least 50%,more preferably at least 75% of the main direction of extension of thepharmaceutical dosage form, the latter being defined as the maximaldistance between two points on the surface of the pharmaceutical dosageform.

Preferably, E₁ and E₂ assume an angle with one another of from 10 to170°, more preferably 20 to 160°, still more preferably 30 to 150°, yetmore preferably 40 to 140°, most preferably 50 to 130°, and inparticular 60 to 120°. In a particularly preferred embodiment, E₁ isorthogonal to E₂.

Preferably, E₂ is the main direction (principal direction) of extensionof the pharmaceutical dosage form, i.e., B₂ can preferably be measuredby placing the pharmaceutical dosage form between the jaws of themeasuring device so that the two jaws have the maximum distance from oneanother but are each in contact the pharmaceutical dosage form.

In a preferred embodiment, E₁ and E₂, which both are preferablyorthogonal to each another, lie within the main area of extension of thedosage form, which main area of extension preferably also contains thecentre of mass of the dosage form.

In a preferred embodiment, B₂ is below 490 N, below 480 N, below 460 N,below 440 N, or below 420 N; more preferably below 400 N, below 380 N,below 360 N, below 340 N, or below 320 N; still more preferably below300 N, below 280 N, below 260 N, below 240 N or below 220 N.

In another preferred embodiment, B₂ is at least 200 N, at least 220 N,at least 240 N, at least 260 N, or at least 280 N; more preferably atleast 300 N, at least 320 N, at least 340 N, at least 360 N, or at least380 N; still more preferably at least 420 N, at least 440 N, at least460 N, or at least 480 N.

Preferably, the ratio of B₁ to B₂ is within the range of from 100:1 to1.1:1, more preferably 75:1 to 1.2:1, still more preferably 50:1 to1.3:1, yet more preferably 25:1 to 1.4:1, most preferably 10:1 to 1.5:1and in particular 5:1 to 1.6:1.

Preferably, the difference B₁-B₂ is at least 10 N, at least 20 N, atleast 30 N, at least 40 N or at least 50 N, more preferably at least 60N, at least 70 N, at least 80 N or at least 90 N, still more preferablyat least 100 N, at least 125 N, at least 150 N, at least 175 N or atleast 200 N, most preferably at least 250 N, at least 300 N, at least350 N, at least 400 or at least 450 N, and in particular at least 500 N,at least 600 N, at least 750 or at least 1000 N.

In a preferred embodiment of the pharmaceutical dosage form according tothe invention, B₁ and B₂ satisfy one of the following conditions C 1 toC 72:

C B₂ B₁ 1 100 N < B₂ < 500 N 500 N < B₁ 2 100 N < B₂ < 500 N 600 N < B₁3 100 N < B₂ < 500 N 700 N < B₁ 4 100 N < B₂ < 500 N 800 N < B₁ 5 100 N< B₂ < 500 N 900 N < B₁ 6 100 N < B₂ < 500 N 1000 N < B₁ 7 100 N < B₂ <500 N 1500 N < B₁ 8 100 N < B₂ < 500 N 2000 N < B₁ 9 200 N < B₂ < 500 N500 N < B₁ 10 200 N < B₂ < 500 N 600 N < B₁ 11 200 N < B₂ < 500 N 700 N< B₁ 12 200 N < B₂ < 500 N 800 N < B₁ 13 200 N < B₂ < 500 N 900 N < B₁14 200 N < B₂ < 500 N 1000 N < B₁ 15 200 N < B₂ < 500 N 1500 N < B₁ 16200 N < B₂ < 500 N 2000 N < B₁ 17 300 N < B₂ < 500 N 500 N < B₁ 18 300 N< B₂ < 500 N 600 N < B₁ 19 300 N < B₂ < 500 N 700 N < B₁ 20 300 N < B₂ <500 N 800 N < B₁ 21 300 N < B₂ < 500 N 900 N < B₁ 22 300 N < B₂ < 500 N1000 N < B₁ 23 300 N < B₂ < 500 N 1500 N < B₁ 24 300 N < B₂ < 500 N 2000N < B₁ 25 400 N < B₂ < 500 N 500 N < B₁ 26 400 N < B₂ < 500 N 600 N < B₁27 400 N < B₂ < 500 N 700 N < B₁ 28 400 N < B₂ < 500 N 800 N < B₁ 29 400N < B₂ < 500 N 900 N < B₁ 30 400 N < B₂ < 500 N 1000 N < B₁ 31 400 N <B₂ < 500 N 1500 N < B₁ 32 400 N < B₂ < 500 N 2000 N < B₁ 33 100 N < B₂ <400 N 500 N < B₁ 34 100 N < B₂ < 400 N 600 N < B₁ 35 100 N < B₂ < 400 N700 N < B₁ 36 100 N < B₂ < 400 N 800 N < B₁ 37 100 N < B₂ < 400 N 900 N< B₁ 38 100 N < B₂ < 400 N 1000 N < B₁ 39 100 N < B₂ < 400 N 1500 N < B₁40 100 N < B₂ < 400 N 2000 N < B₁ 41 200 N < B₂ < 400 N 500 N < B₁ 42200 N < B₂ < 400 N 600 N < B₁ 43 200 N < B₂ < 400 N 700 N < B₁ 44 200 N< B₂ < 400 N 800 N < B₁ 45 200 N < B₂ < 400 N 900 N < B₁ 46 200 N < B₂ <400 N 1000 N < B₁ 47 200 N < B₂ < 400 N 1500 N < B₁ 48 200 N < B₂ < 400N 2000 N < B₁ 49 300 N < B₂ < 400 N 500 N < B₁ 50 300 N < B₂ < 400 N 600N < B₁ 51 300 N < B₂ < 400 N 700 N < B₁ 52 300 N < B₂ < 400 N 800 N < B₁53 300 N < B₂ < 400 N 900 N < B₁ 54 300 N < B₂ < 400 N 1000 N < B₁ 55300 N < B₂ < 400 N 1500 N < B₁ 56 300 N < B₂ < 400 N 2000 N < B₁ 57 100N < B₂ < 300 N 500 N < B₁ 58 100 N < B₂ < 300 N 600 N < B₁ 59 100 N < B₂< 300 N 700 N < B₁ 60 100 N < B₂ < 300 N 800 N < B₁ 61 100 N < B₂ < 300N 900 N < B₁ 62 100 N < B₂ < 300 N 1000 N < B₁ 63 100 N < B₂ < 300 N1500 N < B₁ 64 100 N < B₂ < 300 N 2000 N < B₁ 65 200 N < B₂ < 300 N 500N < B₁ 66 200 N < B₂ < 300 N 600 N < B₁ 67 200 N < B₂ < 300 N 700 N < B₁68 200 N < B₂ < 300 N 800 N < B₁ 69 200 N < B₂ < 300 N 900 N < B₁ 70 200N < B₂ < 300 N 1000 N < B₁ 71 200 N < B₂ < 300 N 1500 N < B₁ 72 200 N <B₂ < 300 N 2000 N < B₁

Further preferred embodiments C 73 to C 96 are summarized in the tablehere below:

C B₂ B₁ 73 320 N < B₂ < 420 N 500 N < B₁ 74 320 N < B₂ < 420 N 600 N <B₁ 75 320 N < B₂ < 420 N 700 N < B₁ 76 320 N < B₂ < 420 N 800 N < B₁ 77320 N < B₂ < 420 N 900 N < B₁ 78 320 N < B₂ < 420 N 1000 N < B₁ 79 320 N< B₂ < 420 N 1500 N < B₁ 80 320 N < B₂ < 420 N 2000 N < B₁ 81 330 N < B₂< 420 N 500 N < B₁ 82 330 N < B₂ < 420 N 600 N < B₁ 83 330 N < B₂ < 420N 700 N < B₁ 84 330 N < B₂ < 420 N 800 N < B₁ 85 330 N < B₂ < 420 N 900N < B₁ 86 330 N < B₂ < 420 N 1000 N < B₁ 87 330 N < B₂ < 420 N 1500 N <B₁ 88 330 N < B₂ < 420 N 2000 N < B₁ 89 340 N < B₂ < 420 N 500 N < B₁ 90340 N < B₂ < 420 N 600 N < B₁ 91 340 N < B₂ < 420 N 700 N < B₁ 92 340 N< B₂ < 420 N 800 N < B₁ 93 340 N < B₂ < 420 N 900 N < B₁ 94 340 N < B₂ <420 N 1000 N < B₁ 95 340 N < B₂ < 420 N 1500 N < B₁ 96 340 N < B₂ < 420N 2000 N < B₁

Due to the property B₂<B₁, the pharmaceutical dosage form according tothe invention preferably has anisotropic mechanical properties, i.e., ismechanically weakened with respect of at least one of its directions ofextension (E₂) compared to its mechanical strength with respect of atleast another of its directions of extension (E₁). In a preferredembodiment, the quality of the mechanical weakening is such that thepharmaceutical dosage form may be fractured once by exerting asufficient amount of force in direction of extension E₂, but the thusobtained fragments are substantially break resistant in any (each andevery) of their directions of extension, i.e., may not be fractured anyfurther by exerting the same amount of force in any (each and every) oftheir directions of extension. Preferably, said amount of force is 400N, 500 N, 600 N, 700 N, 800 N, 900 N, 1000 N, 1100 N, 1200 N, 1300 N,1400 N, or 1500 N. In consequence, according to this embodiment thepharmaceutical dosage form may be fractured once by exerting asufficient amount of force in direction of extension E₂, but may not befractured any further unless the exerted force is increased. Preferably,the number of fragments that are obtained when the pharmaceutical dosageform is fractured once is limited, preferably only two, three, four,five or six fragments, preferably of substantially identical ordifferent size and/or weight, are obtained.

In a preferred embodiment, the surface S [mm²] to weight W [mg] ratioS/W of the pharmaceutical dosage form according to the invention is atleast 0.50 mm²/mg. Preferably, S/W is at least 0.51, at least 0.52, atleast 0.53, at least 0.54 or at least 0.55; more preferably at least0.56, at least 0.57, at least 0.58, at least 0.59 or at least 0.60;still more preferably at least 0.61, at least 0.62, at least 0.63, atleast 0.64 or at least 0.65; yet more preferably at least 0.66, at least0.67, at least 0.68, at least 0.69 or at least 0.70; most preferably atleast 0.705, at least 0.710, at least 0.715, at least 0.720, at least0.725, at least 0.730, at least 0.735, at least 0.740, at least 0.745 orat least 0.750; and in particular at least 0.755, at least 0.760, atleast 0.765, at least 0.770, at least 0.775, at least 0.780, at least0.785, at least 0.790, at least 0.795 or at least 0.80 mm²/mg.

In a preferred embodiment, the pharmaceutical dosage form according tothe invention has a total surface S defined by the formula

S≧A·W ^(2/3),

wherein A is at least 4.5, i.e. S≧4.5·W^(2/3).

For example, when the pharmaceutical dosage form according to theinvention has a total weight of 623 mg, its total surface S ispreferably at least 328 mm² (4.5·623^(2/3)) and when the pharmaceuticaldosage form according to the invention has a total weight of 983 mg, itstotal surface S is preferably at least 445 mm² (4.5·983^(2/3)).

Methods for measuring the total surface of a pharmaceutical dosage formare known to the skilled artisan. For example, the total surface may becalculated from the three dimensional extension of the pharmaceuticaldosage form based on simple geometrical considerations (cf., e.g.,Eudragit® Application Guidelines, 10th edition, July/2007, Röhm GmbH,Darmstadt).

For example, the geometry of the conventional tablet that is depicted inFIG. 11 may be described by a cylindrical element (53) that is locatedbetween two spherical caps (54 a) and (54 b). The volumes V(53), V(54 a)and V(54 b) as well as the surfaces S(53), S(54 a) and S(54 b) can becalculated according to the following formulas:

V(53)=πr ₂ ² h ₂

V(54a)=V(54b)= 1/6πh ₁(3r ² +h ₁ ²)

V _(t) =V(53)+V(54a)+V(54b)

S(53)=2πr ₂ h ₂

S(54a)=S(54b)=2πr ₁ h ₁

S _(t) =S(53)+S(54a)+S(54b)

In approximation, the pharmaceutical dosage form may also be mentallydivided into a plurality of identical cubic volume elements of suitablesize (voxels) and the total surface may be determined by counting thesquared area elements (pixels) being located at the surface. Thisapproximation is further illustrated in FIG. 12 where the pharmaceuticaldosage form according to FIG. 8B) is divided into a plurality of voxels(55).

Preferably, when measuring the total surface of the pharmaceuticaldosage form, the micro-fine structure of the pharmacologically activecompound (A) and of all other constituents of the dosage form includingpolymers and pharmaceutical excipients, e.g. their porosity, is nottaken into account. For the purpose of the specification, the term“surface” of the pharmaceutical dosage form preferably refers to themacroscopic surface (outer dimensions, silhouette). In other words, forthe purpose of determining the surface of the pharmaceutical dosageform, the surface structure is preferably considered perfectly smooth.

In a preferred embodiment of the pharmaceutical dosage form according tothe invention, A is 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5,5.6, 5.7, 5.8, 5.9 or 6.0; more preferably 6.05, 6.1, 6.15, 6.2, 6.25,6.3, 6.35, 6.4, 6.45, 6.5, 6.55, 6.6, 6.65, 6.7, 6.75, 6.8, 6.85, 6.9,6.95, 7.0, 7.05, 7.1, 7.15, 7.2, 7.25, 7.3, 7.35, 7.4, 7.45 or 7.5.

In another preferred embodiment of the pharmaceutical dosage formaccording to the invention, A is 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3,8.4, 8.5, 8.6, 8.7, 8.8, 8.9 or 9.0; more preferably 9.1, 9.2, 9.3, 9.4,9.5, 9.6, 9.7, 9.8, 9.9, 10.0, 10.1, 10.2, 10.3, 10.4 or 10.5; mostpreferably 10.6, 10.7, 10.8, 10.9, 11.0, 11.1, 11.2, 11.3, 11.4, 11.5,11.6, 11.7, 11.8, 11.9 or 12.0; and in particular 12.1, 12.2, 12.3,12.4, 12.5, 12.6, 12.7, 12.8, 12.9, 13.0, 13.1, 13.2, 13.3, 13.4 or13.5.

In a preferred embodiment, the total surface S of the pharmaceuticaldosage form according to the invention satisfies the followingrequirement

B·W ^(2/3) ≧S≧A·W ^(2/3)

-   -   where        -   A and W are defined as above and        -   B is at most 20, more preferably at most 19, still more            preferably at most 18, yet more preferably at most 17, most            preferably at most 16 and in particular at most 15.

In a preferred embodiment, the total surface S of the pharmaceuticaldosage form according to the invention is at least 50 mm², at least 75mm², at least 100 mm², at least 125 mm², at least 150 mm², at least 175mm² or at least 200 mm²; more preferably at least 225 mm², at least 250mm², at least 275 mm², at least 300 mm², at least 325 mm², at least 350mm², at least 375 mm² or at least 400 mm²; still more preferably atleast 425 mm², at least 450 mm², at least 475 mm², at least 500 mm², atleast 525 mm²; at least 550 mm², at least 575 mm² or at least 600 mm²;yet more preferably at least 625 mm², at least 650 mm², at least 675mm², at least 700 mm², at least 725 mm², at least 750 mm², at least 775mm² or at least 800 mm²; most preferably at least 825 mm², at least 850mm², at least 875 mm², at least 900 mm², at least 925 mm², at least 950mm², at least 975 mm² or at least 1000 mm²; and in particular at least1025 mm², at least 1050 mm², at least 1075 mm², at least 1100 mm², atleast 1125 mm², at least 1150 mm², at least 1175 mm² or at least 1200mm².

In a preferred embodiment, the total surface S of the pharmaceuticaldosage form according to the invention is at most 1500 mm², morepreferably at most 1400 mm², still more preferably at most 1300 mm², yetmore preferably at most 1200 mm², most preferably at most 1100 mm², andin particular at most 1000 mm².

In a preferred embodiment the pharmaceutical dosage form according tothe invention is manufactured, particularly shaped, by means of aso-called H-plunger. The silhouette of a dosage form obtainable by meansof such a H-plunger is schematically illustrated in FIG. 10. H-plungersof suitable size and shape are commercially available. Typically, thevolume and the surface of the dosage forms that are obtainable by agiven H-plunger can be calculated with a formula usually provided by themanufacturer of the H-plunger.

For example, Notter GmbH, Germany offers a H-plunger forming a volume of94.3+171.6 h [mm³] and a surface of 382+52.3 h [mm²], where h is theheight of the dosage form (corresponding to distance b₂ in FIG. 10).Therefore, for example, when shaping 650 mg of a compacted compositionhaving an overall density of 1.000 mg/mm³ with such H-plunger, a dosageform is obtained having a height of h=(650-94.3)/171.6=3.24 mm. Thus,said dosage form has a surface of 382+52.3·3.24=551 mm². When A=4.5, therequirement of 551 mm²≧4.5 650^(2/3) (=337.6 mm²) is satisfied. When Ais about 7.3, the requirement of 551 mm²≧7.3 650^(2/3) (=547 mm²) isstill satisfied, but when A is 7.4, the requirement 551 mm²≧7.4650^(2/3) (=555 mm²) is not satisfied.

In a preferred embodiment, the pharmaceutical dosage form according tothe invention has a total weight W of at least 50 mg, at least 75 mg, atleast 100 mg, at least 125 mg or at least 150 mg; more preferably atleast 175 mg, at least 200 mg, at least 225 mg, at least 250 mg or atleast 275 mg; still more preferably at least 300 mg, at least 325 mg, atleast 350 mg, at least 375 mg or at least 400 mg; yet more preferably atleast 425 mg, at least 450 mg, at least 475 mg, at least 500 mg or atleast 525 mg; most preferably at least 550 mg, at least 575 mg, at least600 mg, at least 625 mg or at least 650 mg; and in particular at least675 mg, at least 700 mg, at least 725 mg, at least 750 mg or at least775 mg. Preferably, the total weight of the pharmaceutical dosage formaccording to the invention is within the range from 0.01 g to 1.5 g,more preferably 0.05 g to 1.2 g, still more preferably 0.1 g to 1.0 g,most preferably 0.2 g to 0.9 g and in particular 0.25 g to 0.8 g.

Once the breaking strength of the pharmaceutical dosage form has beenmeasured in a particular direction of extension, its tensile strength insaid direction of extension may be calculated taking into account theouter shape of the dosage form. For example, the tensile strength ofconventional tablets can be calculated according to the followingequation: T S=2×P/π×D×t, where TS is the tensile strength (N·cm⁻², MPa),P is the breaking strength of the tablet (N), D is the tablet diameter(cm), and t is the tablet thickness (cm). The skilled person knows howto modify the above formula when modifying the outer shape of the dosageform. In this regard it can be referred to, e.g., J. T. Fell et al., JPharm Sci. 1970, 59, 688-691; M. P. Summers et al., J Pharm Sci., 1977,66, 1172-1175; and P. N. Davies et al., Eur J Pharm Biopharm. 2007,67(1), 268-76.

Preferably, the pharmaceutical dosage form according to the inventionhas a tensile strength of at least 2.5 N/cm², at least 3.0 N/cm², atleast 3.5 N/cm², at least 4.0 N/cm², at least 4.5 N/cm², at least 5.0N/cm², at least 6.0 N/cm², at least 7.5 N/cm², at least 10.0 N/cm², atleast 12.5 N/cm² or at least 15.0 N/cm²; more preferably at least 17.5N/cm², at least 20.0 N/cm², at least 22.5 N/cm² or at least 25.0 N/cm²;still more preferably at least 27.5 N/cm², at least 30.0 N/cm², at least32.5 N/cm² or at least 35.0 N/cm²; yet more preferably at least 37.5N/cm², at least 40.0 N/cm², at least 42.5 N/cm² or at least 45.0 N/cm²;most preferably at least 47.5 N/cm², at least 50.0 N/cm², at least 52.5N/cm² or at least 55.0 N/cm²; and in particular at least 57.5 N/cm², atleast 60.0 N/cm², at least 62.5 N/cm² or at least 65.0 N/cm²; preferablyat least in direction of extension E₁.

The pharmaceutical dosage forms according to the invention preferablyexhibit high impact strength.

For example, the falling impact strength of the pharmaceutical dosageforms is preferably about 0%. The falling impact strength is a breakageratio obtained when a tablet is allowed to fall from the height of 50 cmonto a stainless steel plate and defined by: {(broken tablets)/(testedtablets)} 100(%).

Preferably, the impact strength of the pharmaceutical dosage formaccording to the invention is sufficiently high so that it cannot becomminuted by means of a hammer. Preferably, when applying five manualhammer strokes by means of a hammer having a weight of 500 g, thepharmaceutical dosage form cannot be comminuted. In a preferredembodiment, the pharmaceutical dosage form does not only exhibit thisimpact strength at ambient temperature, but also below +4° C.(refrigerator), more preferably below −33° C. (deep freezer), mostpreferably below −77° C. (dry ice) and in particular below −190° C.(liquid nitrogen).

Preferably, the pharmaceutical dosage form according to the inventionexhibits a cutting resistance of at least 75 N, more preferably at least100 N, still more preferably at least 125 N, yet more preferably atleast 140 N, most preferably at least 150 N and in particular at least160 N, in at least one direction of extension, preferably in directionof extension E₁. Preferably, the cutting test is performed according toDIN EN ISO 604, preferably at a testing speed of 30 mm/min and by meansof a universal glass cleaning blade having a thickness of 0.30 mm.

The friability of the pharmaceutical dosage form according to theinvention can be measured, e.g., by means of a Pharmatest PTF-Eapparatus (Hainburg, Germany) following, e.g., the European Pharmacopeia(Ph. Eur.) specifications. Preferably, the friability of thepharmaceutical dosage form according to the invention is at most 0.50%,more preferably at most 0.40%, still more preferably at most 0.30%, yetmore preferably at most 0.20%, most preferably at most 0.10% and inparticular at most 0.05%.

In a preferred embodiment the pharmaceutical dosage form according tothe invention has an overall density of at least 0.80 or at least 0.85g/cm³, more preferably at least 0.90 or at least 0.95 g/cm³, still morepreferably at least 1.00, at least 1.05 or at least 1.10 g/cm³, mostpreferably in the range from 0.80 to 1.35 g/cm³, and in particular inthe range from 0.95 to 1.25 g/cm³.

In a preferred embodiment, the pharmaceutical dosage form according tothe invention has an overall density within the range of 1.00±0.30g/cm³, more preferably 1.00±0.25 g/cm³, still more preferably 1.00±0.20g/cm³, yet more preferably 1.00±0.15 g/cm³, most preferably 1.00±0.10g/cm³, and in particular 1.00±0.05 g/cm³. In another preferredembodiment, the pharmaceutical dosage form according to the inventionhas an overall density within the range of 1.10±0.30 g/cm³, morepreferably 1.10±0.25 g/cm³, still more preferably 1.10±0.20 g/cm³, yetmore preferably 1.10±0.15 g/cm³, most preferably 1.10±0.10 g/cm³, and inparticular 1.10±0.05 g/cm³. In still another preferred embodiment, thepharmaceutical dosage form according to the invention has an overalldensity within the range of 1.20±0.30 g/cm³, more preferably 1.20±0.25g/cm³, still more preferably 1.20±0.20 g/cm³, yet more preferably1.20±0.15 g/cm³, most preferably 1.20±0.10 g/cm³, and in particular1.20±0.05 g/cm³. Preferably, the overall density of the pharmaceuticaldosage form according to the invention is 1.00±0.02 g/cm³, 1.02±0.02g/cm³, 1.04±0.02 g/cm³, 1.06±0.02 g/cm³, 1.08±0.02 g/cm³, 1.10±0.02g/cm³, 1.12±0.02 g/cm³, 1.14±0.02 g/cm³, 1.16±0.02 g/cm³, 1.18±0.02g/cm³, 1.20±0.02 g/cm³, 1.22±0.02 g/cm³, 1.24±0.02 g/cm³, 1.26±0.02g/cm³, 1.28±0.02 g/cm³, 1.30±0.02 g/cm³, 1.32±0.02 g/cm³, 1.34±0.02g/cm³, 1.36±0.02 g/cm³, 1.38±0.02 g/cm³, or 1.40±0.02 g/cm³.

Preferably, the pharmaceutical dosage form according to the invention ischaracterized by a comparatively homogeneous distribution of density.Preferably, the densities of two segments of the pharmaceutical dosageform having a volume of 1.0 mm³ each, deviate from one another by notmore than ±10%, more preferably not more than more than ±7.5%, stillmore preferably not more than ±5.0%, most preferably not more than±2.5%, and in particular not more than ±1.0%. When the pharmaceuticaldosage form is film coated, said two segments of the pharmaceuticaldosage form having a volume of 1.0 mm³ each are preferably segments ofthe core, i.e. do not contain any coating material.

In a preferred embodiment, the pharmaceutical dosage form according tothe invention is thermoformed, preferably by extrusion, although alsoother methods of thermoforming may be used in order to manufacture thedosage form according to the invention such as press-molding at elevatedtemperature.

The pharmaceutical dosage form according to the invention contains apharmacologically active compound (A), for the purpose of thespecification also referred to as “component (A)”

Preferred pharmacologically active compounds (A) have already beenmentioned as pharmaceutically active ingredients and pharmaceuticallyactive ingredients with potential for abuse in connection with the firstand second aspects of the invention.

In a preferred embodiment, under ambient conditions, the solubility ofcomponent (A) in pure water is at least 1.0 g/L, more preferably atleast 5.0 g/L, still more preferably at least 10 g/L, yet morepreferably at least 25 g/L, most preferably at least 50 g/L and inparticular at least 100 g/L.

In another preferred embodiment, under ambient conditions, thesolubility of component (A) in pure water is at most 1.0 g/L, morepreferably at most 0.5 g/L, still more preferably at most 0.1 g/L, yetmore preferably at most 0.05 g/L, most preferably at most 0.01 g/L andin particular at most 0.005 g/L.

In a preferred embodiment, the pharmaceutical dosage form according tothe invention contains a pharmaceutically effective amount of apharmacologically active compound (A), which justifies use of thepharmaceutical dosage form as a pharmaceutical preparation and is thecause of the activity thereof. Pharmacologically active compounds (A)which may in principle be considered in the pharmaceutical dosage formaccording to the invention are any known pharmaceutical substances,wherein these substances may be present in the pharmaceutical dosageform according to the invention as such, in the form the derivativesthereof, in particular esters or ethers, or in each case in the form ofcorresponding physiologically acceptable compounds, in particular in theform of the corresponding salts or solvates thereof, as racemates or ina form enriched in one or more stereoisomers (enantiomers ordiastereomers).

The pharmaceutical dosage form according to the invention is suitablefor the administration of a number of pharmacologically active compounds(A) in a single pharmaceutical dosage form. Preferably, thepharmaceutical dosage form contains only one particularpharmacologically active compound (A).

The amount of the pharmacologically active compound (A), based on thetotal amount of the pharmaceutical dosage form, is preferably within therange from 0.01 to 95 wt.-%, more preferably from 0.5 to 80 wt.-%, stillmore preferably 1.0 to 70 wt.-%, most preferably 5.0 to 60 wt.-% and inparticular 10 to 50 wt.-%. In a preferred embodiment it is more than 20wt.-%.

In a preferred embodiment the pharmaceutical dosage form according tothe invention contains a psychotropically acting substance as thepharmacologically active compound (A).

The person skilled in the art knows which substances have a psychotropicaction. Substances which influence psychological processes commonly havea psychotropic action, i.e. they act specifically on psychologicalfunctions. Substances with a psychotropic action may thus influencemood, either raising or lowering it. For the purpose of the description,substances with a psychotropic action include in particular opioids,stimulants, tranquillisers (e.g. barbiturates and benzodiazepines) andother narcotics. Substances with a psychotropic action preferablycomprise substances which, in particular when improperly administered(in particular with the intention of abuse), cause an acceleratedincrease in active compound levels relative to proper oraladministration, giving the abuser the desired effect, namely the “kick”or “rush”. This kick is also obtained if the powdered pharmaceuticaldosage form is administered nasally, i.e. is sniffed. Substances with apsychotropic action are preferably substances which (in the appropriatedose and pharmaceutical dosage form and when administered appropriately)influence human mental activity and/or sensory perception in such a waythat they are fundamentally suited to abuse.

In particular, the pharmaceutical dosage form according to the inventionpreferably contains a psychotropically acting substance selected fromthe group consisting of opioids [A07DA, N01AH, N02A, R05DA, R05FA,];barbiturates [N01AF, N01AG, N03AA]; benzodiazepine derivatives [N03AE];agents for treating opiate dependency [N07BC]; anxiolytics [N05B];hypnotics and sedatives [N05C]; psychostimulants, agents for treatingattention-deficit/hyperactivity disorder (ADHD) and nootropics [N06B];antiemetics [A04A]; antiobesity preparations excluding diet products[A08A]; centrally acting muscle relaxants [M03B]; and antidotes [V03AB].The abbreviations stated in square brackets here correspond to the ATCIndex (“Gelbe Liste”), as used by the WHO for classifying pharmaceuticalsubstances (preferred version: 2007 or 2008).

The pharmaceutical dosage form according to the invention preferablycontains a psychotropically acting substance selected from the groupconsisting of opioids, vanilloid receptor modulators,serotonin/norepinephrine/dopamine modulators, GABA modulators, NMDAantagonists, ion channel blockers/modulators, cannabionoids, and otherNSAIDS.

The following opiates, opioids, tranquillisers or other narcotics aresubstances with a psychotropic action, i.e. have a potential of abuse,and hence are preferably contained in the pharmaceutical dosage formaccording to the invention: alfentanil, allobarbital, allylprodine,alphaprodine, alprazolam, amfepramone, amphetamine, amphetaminil,amobarbital, anileridine, apocodeine, axomadol, barbital, bemidone,benzylmorphine, bezitramide, bromazepam, brotizolam, buprenorphine,butobarbital, butorphanol, camazepam, carfentanil,cathine/D-norpseudoephedrine, chlordiazepoxide, clobazam clofedanol,clonazepam, clonitazene, clorazepate, clotiazepam, cloxazolam, cocaine,codeine, cyclobarbital, cyclorphan, cyprenorphine, delorazepam,desomorphine, dextromoramide, dextropropoxyphene, dezocine, diampromide,diamorphone, diazepam, dihydrocodeine, dihydromorphine, dihydromorphone,dimenoxadol, dimephetamol, dimethylthiambutene, dioxaphetylbutyrate,dipipanone, dronabinol, eptazocine, estazolam, ethoheptazine,ethylmethylthiambutene, ethyl loflazepate, ethylmorphine, etonitazene,etorphine, fencamfamine, fenethylline, fenpipramide, fenproporex,fentanyl, fludiazepam, flunitrazepam, flurazepam, halazepam,haloxazolam, heroin, hydrocodone, hydromorphone, hydroxypethidine,isomethadone, hydroxymethylmorphinan, ketazolam, ketobemidone,levacetylmethadol (LAAM), levomethadone, levorphanol,levophenacylmorphane, levoxemacin, lisdexamfetamine dimesylate,lofentanil, loprazolam, lorazepam, lormetazepam, mazindol, medazepam,mefenorex, meperidine, meprobamate, metapon, meptazinol, metazocine,methylmorphine, metamphetamine, methadone, methaqualone,3-methylfentanyl, 4-methylfentanyl, methylphenidate,methylphenobarbital, methyprylon, metopon, midazolam, modafinil,morphine, myrophine, nabilone, nalbuphene, nalorphine, narceine,nicomorphine, nimetazepam, nitrazepam, nordazepam, norlevorphanol,normethadone, normorphine, norpipanone, opium, oxazepam, oxazolam,oxycodone, oxymorphone, Papaver somniferum, papavereturn, pernoline,pentazocine, pentobarbital, pethidine, phenadoxone, phenomorphane,phenazocine, phenoperidine, piminodine, pholcodeine, phenmetrazine,phenobarbital, phentermine, pinazepam, pipradrol, piritramide, prazepam,profadol, proheptazine, promedol, properidine, propoxyphene,remifentanil, secbutabarbital, secobarbital, sufentanil, tapentadol,temazepam, tetrazepam, tilidine (cis and trans), tramadol, triazolam,vinylbital, N-(1-methyl-2-piperidinoethyl)-N-(2-pyridyl)propionamide,(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)phenol,(1R,2R,4S)-2-(dimethylamino)methyl-4-(p-fluorobenzyloxy)-1-(m-methoxyphenyl)cyclohexanol,(1R,2R)-3-(2-dimethylaminomethyl-cyclohexyl)phenol,(1S,2S)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol,(2R,3R)-1-dimethylamino-3(3-methoxyphenyl)-2-methyl-pentan-3-ol,(1RS,3RS,6RS)-6-dimethylaminomethyl-1-(3-methoxyphenyl)-cyclohexane-1,3-diol,preferably as racemate,3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)phenyl2-(4-isobutyl-phenyl)propionate,3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)phenyl2-(6-methoxy-naphthalen-2-yl)propionate,3-(2-dimethylaminomethyl-cyclohex-1-enyl)-phenyl2-(4-isobutyl-phenyl)propionate,3-(2-dimethylaminomethyl-cyclohex-1-enyl)-phenyl2-(6-methoxy-naphthalen-2-yl)propionate,(RR—SS)-2-acetoxy-4-trifluoromethyl-benzoic acid3-(2-dimethylaminomethyl-1-hydroxycyclohexyl)-phenyl ester,(RR—SS)-2-hydroxy-4-trifluoromethyl-benzoic acid3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl ester,(RR—SS)-4-chloro-2-hydroxybenzoic acid3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl ester,(RR—SS)-2-hydroxy-4-methyl-benzoic acid3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl ester,(RR—SS)-2-hydroxy-4-methoxy-benzoic acid3-(2-dimethylaminomethyl-1-hydroxycyclohexyl)-phenyl ester,(RR—SS)-2-hydroxy-5-nitro-benzoic acid3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl ester,(RR—SS)-2′,4′-difluoro-3-hydroxybiphenyl-4-carboxylic acid3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl ester, andcorresponding stereoisomeric compounds, in each case the correspondingderivatives thereof, physiologically acceptable enantiomers,stereoisomers, diastereomers and racemates and the physiologicallyacceptable derivatives thereof, e.g. ethers, esters or amides, and ineach case the physiologically acceptable compounds thereof, inparticular the salts thereof and solvates, e.g. hydrochlorides.

In a preferred embodiment the pharmaceutical dosage form according tothe invention contains an opioid selected from the group consisting ofDPI-125, M6G (CE-04-410), ADL-5859, CR-665, NRP290 and sebacoyldinalbuphine ester.

In a preferred embodiment the pharmaceutical dosage form according tothe invention contains one pharmacologically active compound (A) or morepharmacologically active compounds (A) selected from the groupconsisting of oxymorphone, hydromorphone and morphine.

In another preferred embodiment, the pharmacologically active compound(A) is selected from the group consisting of tapentadol, faxeladol andaxomadol.

For the purposes of the description, the pharmacokinetic parameters,which may be determined from the blood plasma concentrations of thepharmacologically active compound (A), are defined as follows:

C_(max) maximum measured plasma concentration of the active ingredientafter single administration (≡average peak plasma level) t_(max)interval of time from administration of the active ingredient untilC_(max) is reached t_(1/2) half-life AUC_(0-∞) total area under thecurve

The above parameters are in each case stated as mean values of theindividual values for all investigated patients/test subjects.

A person skilled in the art knows how the pharmacokinetic parameters ofthe active ingredient may be calculated from the measured concentrationsof the active ingredient in the blood plasma. In this connection,reference may be made, for example, to Willi Cawello (ed.) Parametersfor Compartment-free Pharmacokinetics, Shaker Verlag Aachen (1999).

In a preferred embodiment, after preferably oral administration of thedosage form according to the invention, in vivo the average peak plasmalevel (C_(max)) is on average reached after t_(max) 4.0±2.5 h, morepreferably after t_(max) 4.0±2.0 h, still more preferably after t_(max)4.0±1.5 h, most preferably after t_(max) 4.0±1.0 h and in particularafter t_(max) 4.0±0.5 h. In another preferred embodiment, afterpreferably oral administration of the dosage form according to theinvention, in vivo the average peak plasma level (C_(max)) is on averagereached after t_(max) 5.0±2.5 h, more preferably after t_(max) 5.0±2.0h, still more preferably after t_(max) 5.0±1.5 h, most preferably aftert_(max) 5.0±1.0 h and in particular after t_(max) 5.0±0.5 h. In stillanother preferred embodiment, after preferably oral administration ofthe dosage form according to the invention, in vivo the average peakplasma level (C_(max)) is on average reached after t_(max) 6.0±2.5 h,more preferably after t_(max) 6.0±2.0 h, still more preferably aftert_(max) 6.0±1.5 h, most preferably after t_(max) 6.0±1.0 h and inparticular after t_(max) 6.0±0.5 h.

In a preferred embodiment, the average value for t₁₁₂ after preferablyoral administration of the dosage form according to the invention invivo is 4.3±2.5 h, more preferably 4.3±2.0 h, still more preferably4.3±1.5 h, most preferably 4.3±1.0 h, and in particular 4.3±0.5 h. Inanother preferred embodiment, the average value for t₁₁₂ afterpreferably oral administration of the dosage form according to theinvention in vivo is preferably 5.3±2.5 h, more preferably 5.3±2.0 h,still more preferably 5.3±1.5 h, most preferably 5.3±1.0 h, and inparticular 5.3±0.5 h. In still another preferred embodiment, the averagevalue for t₁₁₂ after preferably oral administration of the dosage formaccording to the invention in vivo is preferably 6.3±2.5 h, morepreferably 6.3±2.0 h, still more preferably 6.3±1.5 h, most preferably6.3±1.0 h, and in particular 6.3±0.5 h.

In a preferred embodiment, the pharmacologically active compound (A) istapentadol or a physiologically acceptable salt thereof, and afterpreferably oral administration of the dosage form according to theinvention, in vivo the average value for the total area under the curveAUC_(0-∞) is 825±600 ng·h/mL, more preferably 825±500 ng·h/mL, stillmore preferably 825±400 ng·h/mL, yet more preferably 825±300 ng·h/mL,most preferably 825±200 ng·h/mL, and in particular 825±100 ng·h/mL. Inanother preferred embodiment, the pharmacologically active compound (A)is tapentadol or a physiologically acceptable salt thereof, and afterpreferably oral administration of the dosage form according to theinvention, in vivo the average value for the total area under the curveAUC_(0-∞) is 1100±600 ng·h/mL, more preferably 1100±500 ng·h/mL, stillmore preferably 1100±400 ng·h/mL, yet more preferably 1100±300 ng·h/mL,most preferably 1100±200 ng·h/mL, and in particular 1100±100 ng·h/mL.

In a preferred embodiment, the pharmacologically active compound (A) istapentadol or a physiologically acceptable salt thereof, and afterpreferably oral administration of the dosage form according to theinvention, in vivo the average value of C_(max) is 63±40 ng/mL, morepreferably 63±30 ng/mL, still more preferably 63±20 ng/mL, yet morepreferably 63±15 ng/mL, most preferably 63±10 ng/mL and in particular63±5 ng/mL. In another preferred embodiment, the pharmacologicallyactive compound (A) is tapentadol or a physiologically acceptable saltthereof, and after preferably oral administration of the dosage formaccording to the invention, in vivo the average value of C_(max) is89±40 ng/mL, more preferably 89±30 ng/mL, still more preferably 89±20ng/mL, yet more preferably 89±15 ng/mL, most preferably 89±10 ng/mL andin particular 89±5 ng/mL.

In a particularly preferred embodiment the pharmacologically activecompound (A) is tapentadol or a physiologically acceptable salt thereofand the pharmaceutical dosage form according to the invention isbioequivalent to a formulation that contains tapentadol or aphysiologically acceptable salt thereof in a dosage of 200 mg and 250mg, respectively, and is characterized by the following pharmacokineticdata:

Parameter dosage 200 mg dosage 250 mg AUC_(0-∞) 825 ng · h/mL 1096 ng ·h/mL C_(max) 62.5 ng/mL 89.3 ng/mL t_(max) 5.00 h 5.00 h t_(1/2) 5.2 h5.4 h

The skilled person is aware what requirement have to be satisfied inorder to achieve bioequivalence. In this regard it can be referred e.g.to “Note for Guidance on the Investigation of Bioavailability andBioequivalence”, EMEA, London, 26 Jul. 2001 (CPMP/EWP/QWP/1401/98);“Guidance for Industry—Bioavailability and Bioequivalence—Studies forOrally Administered Drug Products—General Considerations”, FDA, BP,Announced in the Federal Register: Volume 68, Number 53/Mar. 19, 2003;and “Guidance for Industry—Statistical Approaches to EstablishingBioequivalence”, FDA, BP, January 2001.

In general, two medicinal products are bioequivalent if they arepharmaceutically equivalent or pharmaceutical alternatives and if theirbioavailabilities after administration in the same molar dose aresimilar to such degree that their effects, with respect to both efficacyand safety, will be essentially the same. Preferably, statistical datashould be analyzed using ANOVA based on a 90% confidence interval. Forexample, as regards AUC-ratio, the 90% confidence interval for thismeasure of relative bioavailability should lie within an acceptanceinterval of 0.80-1.25, and as regards Cmax-ratio, the 90% confidenceinterval for this measure of relative bioavailability should lie withinan acceptance interval of 0.80-1.25.

In a preferred embodiment the pharmaceutical dosage form according tothe invention contains one pharmacologically active compound (A) or morepharmacologically active compounds (A) selected from the groupconsisting of1,1-(3-dimethylamino-3-phenyl-pentamethylen)-6-fluor-1,3,4,9-tetrahydropyrano[3,4-b]indole,in particular its hemicitrate;1,1-[3-dimethylamino-3-(2-thienyl)pentamethylen]-1,3,4,9-tetrahydropyrano[3,4-b]indole,in particular its citrate; and1,1-[3-dimethylamino-3-(2-thienyl)pentamethylen]-1,3,4,9-tetrahydropyrano[3,4-b]-6-fluoro-indole,in particular its hemicitrate. These compounds are known, for example,from WO 2004/043967 or WO 2005/066183. The corresponding descriptionsare hereby introduced as a reference and are deemed to be part of thedisclosure.

In a preferred embodiment, the pharmaceutical dosage form according tothe invention contains no substances which irritate the nasal passagesand/or pharynx, i.e. substances which, when administered via the nasalpassages and/or pharynx, bring about a physical reaction which is eitherso unpleasant for the patient that he/she does not wish to or cannotcontinue administration, for example burning, or physiologicallycounteracts taking of the corresponding active compound, for example dueto increased nasal secretion or sneezing. Further examples of substanceswhich irritate the nasal passages and/or pharynx are those which causeburning, itching, an urge to sneeze, increased formation of secretionsor a combination of at least two of these stimuli. Correspondingsubstances and the quantities thereof which are conventionally to beused are known to the person skilled in the art. Some of the substanceswhich irritate the nasal passages and/or pharynx are accordingly basedon one or more constituents or one or more plant parts of a hotsubstance drug. Corresponding hot substance drugs are known per se tothe person skilled in the art and are described, for example, in“Pharmazeutische Biologie—Drogen and ihre Inhaltsstoffe” by Prof. Dr.Hildebert Wagner, 2nd., revised edition, Gustav Fischer Verlag,Stuttgart-New York, 1982, pages 82 et seq. The corresponding descriptionis hereby introduced as a reference and is deemed to be part of thedisclosure.

The pharmaceutical dosage form according to the invention furthermorepreferably contains no antagonists for the pharmacologically activecompound (A), preferably no antagonists against psychotropic substances,in particular no antagonists against opioids. Antagonists suitable for agiven pharmacologically active compound (A) are known to the personskilled in the art and may be present as such or in the form ofcorresponding derivatives, in particular esters or ethers, or in eachcase in the form of corresponding physiologically acceptable compounds,in particular in the form of the salts or solvates thereof. Thepharmaceutical dosage form according to the invention preferablycontains no antagonists selected from among the group comprisingnaloxone, naltrexone, nalmefene, nalide, nalmexone, nalorphine ornaluphine, in each case optionally in the form of a correspondingphysiologically acceptable compound, in particular in the form of abase, a salt or solvate; and no neuroleptics, for example a compoundselected from among the group comprising haloperidol, promethacine,fluphenazine, perphenazine, levomepromazine, thioridazine, perazine,chlorpromazine, chlorprothixine, zuclopenthixol, flupentixol,prothipendyl, zotepine, benperidol, pipamperone, melperone andbromperidol.

The pharmaceutical dosage form according to the invention furthermorepreferably contains no emetic. Emetics are known to the person skilledin the art and may be present as such or in the form of correspondingderivatives, in particular esters or ethers, or in each case in the formof corresponding physiologically acceptable compounds, in particular inthe form of the salts or solvates thereof. The pharmaceutical dosageform according to the invention preferably contains no emetic based onone or more constituents of ipecacuanha (ipecac) root, for example basedon the constituent emetine, as are, for example, described in“Pharmazeutische Biologie—Drogen and ihre Inhaltsstoffe” by Prof. Dr.Hildebert Wagner, 2nd, revised edition, Gustav Fischer Verlag,Stuttgart, New York, 1982. The corresponding literature description ishereby introduced as a reference and is deemed to be part of thedisclosure. The pharmaceutical dosage form according to the inventionpreferably also contains no apomorphine as an emetic.

Finally, the pharmaceutical dosage form according to the inventionpreferably also contains no bitter substance. Bitter substances and thequantities effective for use may be found in US-2003/0064099 A1, thecorresponding disclosure of which should be deemed to be the disclosureof the present application and is hereby introduced as a reference.Examples of bitter substances are aromatic oils, such as peppermint oil,eucalyptus oil, bitter almond oil, menthol, fruit aroma substances,aroma substances from lemons, oranges, limes, grapefruit or mixturesthereof, and/or denatonium benzoate.

The pharmaceutical dosage form according to the invention accordinglypreferably contains neither substances which irritate the nasal passagesand/or pharynx, nor antagonists for the pharmacologically activecompound (A), nor emetics, nor bitter substances.

In a preferred embodiment the pharmaceutical dosage form according tothe invention contains a non-psychotropically acting substance as thepharmacologically active compound (A).

Particularly preferably the pharmaceutical dosage form according to theinvention contains a pharmacologically active compound (A) or two ormore such compounds selected from the group consisting of

-   -   agents for the treatment and prevention of diseases of the        alimentary system and metabolism [A]; in particular        stomatological preparations [A01], agents for the treatment and        prevention of acid-related disorders [A02], agents for the        treatment and prevention of functional gastrointestinal tract        disorders [A03], serotonin 5HT₃ antagonists [A04 a)A],        antihistamine preparations [A04 a)B], agents for bile and liver        therapy [A05], laxatives [A06], intestinal antiinfectives        [A07A], intestinal adsorbents [A07B], electrolytes with        carbohydrates [A070], intestinal antiinflammatory agents [A07E],        microbial antidiarrhoeals [A07F], digestives including enzymes        [A09], drugs used in diabetes [A10], vitamins [A11], minerals        [A12], anabolic agents for systemic applications [A14] and        appetite stimulants [A15];    -   agents for the treatment and prevention of diseases of the blood        and the blood forming organs [B]; in particular antithrombotic        agents [B01], antihaemorrhagics [B02], antianaemic preparations        [B03] and other haematological agents [B06];    -   agents for the treatment and prevention of diseases of the        cardiovascular system [C]; in particular agents for cardiac        therapy [C01], antihypertensives [C02], diuretics [C03],        peripheral vasodilatators [C04], vasoprotectives [C05],        antihypotensives [C06A], β-adrenoceptor antagonists [C07],        calcium channel blockers [C08], agents acting on the        renin-angiotensin system [C09] and lipid reducing agents [C10];    -   dermatologicals [D]; in particular antifungals for systemic use        [D01B], antipsoriatics for systemic use [D05B], antiacne        preparations for systemic use [D10B];    -   agents for the treatment and prevention of diseases of the        genitourinary system and sex hormones [G]; in particular        gynaecological antiinfectives and antiseptics [G01], oxytocics        [G02A], sympathomimetic labour repressants [G02CA], prolactin        inhibitors [G02CB], hormonal contraceptives for systemic use        [G03] and urologicals [G04];    -   systemic hormone preparations excluding sex hormones and        insulins [H]; in particular pituitary and hypothalamic hormones        and analogue [H01], corticosteroids for systemic use [H02],        thyroid preparations [H03], pancreatic hormones [H04], and        agents for regulating calcium homeostatis [H05];

antiinfectives for systemic use [J]; in particular antibiotics forsystemic use [J01], antimycotics for systemic use [J02],antimycobacterials [J04], antivirals for systemic use [J05], immune seraand immunoglobulins [J06], and vaccines [J07]);

-   -   antineoplastic and immunomodulating agents [L] (in particular        antineoplastistic agents [L01], agents for endocrine therapy        [L02], immunostimulants [L03] and immunosuppressive agents        [L04];    -   agents for the treatment and prevention of diseases of the        musculo-skeletal system [M]; in particular antiinflammatory and        antirheumatic agents [M01], peripherally acting muscle relaxants        [M03A], directly acting muscle relaxants [M03C], antigout        preparations [M04] and agents for the treatment of bone diseases        [M05];    -   agents for the treatment and prevention of diseases of the        nervous system [N]; in particular salicylic acid the derivatives        thereof [N02b)A], pyrazolones [N02b)B], anilides [N02 b)E],        ergot alkaloids [N02CA], corticosteroid derivatives [N02CB],        selective serotonin-5HT₁ agonists [N02CC], hydantoin derivatives        [N03 a)B], oxazolidine derivatives [N03 a)C], succinimide        derivatives [N03 a)D], carboxamide derivatives [N03 a)F], fatty        acid derivatives [N03 a)G], antiparkinson drugs [N04]),        antipsychotics [N05A], antidepressants [N06A], antidementia        drugs [NO₆D], parasympathomimetics [N07A] and antivertigo        preparations [N07C];    -   antiparasitic products, insecticides and repellents [P]; in        particular antiprotozoals [P01], anthelmintics [P02] and        ectoparasiticides, including scabicides, insecticides and        repellents [P03];    -   agents for the treatment and prevention of diseases of the        respiratory system [R]; in particular nasal preparations [R01],        throat preparations [R02], drugs for obstructive airways        diseases [R03], expectorants, excluding combinations with cough        suppressants [R05C] and antihistamines for systemic use [R06];    -   agents for the treatment and prevention of diseases of the        sensory organs [S]; in particular otologicals [S02]; and

general diet products [V06] and therapeutic radiopharmaceuticals [V10],

wherein the abbreviations stated in square brackets here correspond tothe ATC Index, as used by the WHO for classifying pharmaceuticalsubstances (preferred version: 2007 or 2008).

The pharmaceutical dosage form according to the invention preferablycontains one, two or more pharmacologically active compounds (A)selected from the group consisting of 4-aminomethylbenzoic acid,abacavir, abamectin, abciximab, abibendan, abrin, acamprosat, acarbose,acebutolol, aceclidine, aceclofenac, acediasulfone, acemetacin,acenocoumarol, acetazolamide, acetoacetic acid, acetyldigoxin,acetylandromedol, acetylcysteine, β-acetyldigoxin, acetylhistamine,acetylsalicylic acid, acetylthiocholine, aciclovir, acipimox, acitretin,aclarubicin, aconitine, acriflavinium chloride, acrivastine,actinoquinol, acylaminopenicillin, adalimumab, adapalene, adefovir,adefovir dipivoxil, adenosine, adenosine phosphate, adenosinetriphosphate, adipiodone, adrenalin, aescin, agalsidase alfa, agalsidasebeta, agaricic acid, ajmaline, alanine, albendazole, alcuronium,aldesleukin, aldosterone, alemtuzumab, alendronic acid, alfacalcidol,alfuzosin, algeldrate F, alitretinoin, alizapride, allantoin F,allopurinol, allyl isorhodanate, almasilate F, almotriptan,aacetyldigoxin, alprenolol, alprostadil, alteplase, aluminium glycinateF, aluminium hydroxide F, aluminium phosphate F, aluminium triformate,amantadine, ambazone, ambroxol, ambutonium bromide, formic acid,amicacin, amidephrine, amidotrizoic acid, amifostine, amikacin,amiloride, aminoacetic acid, aminoglutethimide, aminophylline,aminoquinuride, amiodarone, amisulpride, amitriptyline, amitryptiline,amlodipine, amorolfine, amoxicillin, amphotericin B, ampicillin,amprenavir, amylmetacresol, amyl nitrite, anagrelide, anakinra,anastrozole, ancrod, anistreplase, antazoline, antithrombin III,apomorphine, apraclonidine, aprepitant, aprindine, aprotinin,arcitumomab, arginine, aripiprazole, arsenic trioxide, artemether,articaine, ascorbic acid, asparagine, L-asparaginase, aspartic acid,atazanavir, atenolol, atomoxetine, atorvastatin, atosiban, atovaquone,atracurium, atracurium besylate, atropine, auranofin, azapropazone,azathioprine, azelaic acid, azelastine, azidothymidine, azithromycin,azlocillin, aztreonam, N2 alanyl levoglutamide, p-aminosalicylic acid,

bacampicillin, bacitracin, baclofen, balsalazide, bambuterol, bamethan,bamipine, barbexaclone, barium sulfate F, barnidipine, basiliximab,batroxobin, becaplermin, beclomethasone, bendamustine, befunolol,bemiparin, benactyzine, benazepril, bencyclane, bendazac,bendroflumethiazide, benproperine, benserazide, benzaseride, benzathine,benzatropine, benzbromarone, benzocaine, benzoyl peroxide, benzyclane,benzydamine, benzylpenicillin, benzylphenyl glycolate, betacarotene,betahistidine, betahistine, betamethasone, bethanechol, betaxolol,bethanechol chloride, betiatide, bevacizumab, bexarotene, bezafibrate,bibenzonium bromide, bicalutamide, bicisate, bifonazole, bimatoprost,biperiden, bisoprolol, bivalirudin, bleomycin, blood clotting factorVII, VIII, IX, X, XIII, bornapine, bornaprine, bortezomib, bosentan,botulinum toxin type B, brimonidine, brinzolamide, brivudin, bromhexine,bromocriptine, bromperidol, brompheniramine, brotizolam, budesonide,budipine, bufexamac, buflomedil, bumetanide, bunazosin, buphenine,bupivacaine, bupranolol, bupropion, buserelin, buspirone, busulfan,butalamine, butanilicaine, butenafine, butethamate, butinoline,butizide, butylscopolaminium,5-chlorcarvacrol, C1 esterase inhibitor, cabergoline, cadexomer iodine,cafedrine, calcipotriol, calcitonin, calcitriol, camylofine, candesartancilexetil, canrenoic acid, capecitabine, capreomycin, capsaicin,captopril, carazolol, carbaldrate F, carbamazepine, carbasalate calcium,carbenoxolone, carbidopa, carbimazole, carbinoxamine, carboplatin,carglumic acid, carmustine, caroverine, carteolol, carvedilol,caspofungin, cefaclor, cefadroxil, cefalexin, cefaloridine, cefamandole,cefazolin, cefdinir, cefepime, cefetametpivotil, cefixime, cefodizime,cefoperazone, cefotaxime, cefotiam, cefoxitin, cefpirome, cefpodoxime,cefpodoxime-proxetil, cefprozil, ceftazidime, ceftibuten, ceftizoxime,ceftriaxone, cefuroxime, celecoxib, celiprolol, certoparin, cetirizine,cetrimide, cetrimonium bromide, cetrorelix, cetuximab, cetylpyridinium,chenodeoxycholic acid, quinidine, quinine, quinine iron citrate F,quinine tannate F, chlorambucil, chloramphenicol, chlorobutynol,chlorhexidine, chlormidazole, chlorobutanol, chloroquine, chloroxylenol,chlorphenamine, chlorphenesin, chlorphenoxamine, chlorpromazine,chlorprotheaxine, chlorprothixine, chlortalidone, chlortetracycline,chlorzoxazone, choline, chondroitin sulfate, choriogonadotropin alfa,chorionic gonadotropin, chrysarobin, chymotrypsin, ciclesonide,cicletanine, ciclopirox, ciclosporin, cidofovir, cilastatin, cilazapril,cimetidine, cinacalcet, cinchocaine, cinnarizine, cinolazepam,ciprofloxacin, cisapride, cisatracurium besylate, cisplatin, citalopram,citicoline, cladribine, clarithromycin, clavulanic acid, clemastine,clenbuterol, clindamycin, clioquinol, clobetasol, clobetasone,clobutinol, clocortolone, clodronic acid, Clofibrate, clomifene,clomipramine, clonazepam, clonidine, clopamide, clopidogrel, clostebolacetate, clostridium botulinum, clotrimazole, cloxiquine, clozapine,cocarboxylase, colchicine, colecalciferol, colesevelam, colestipol,colestyramine, colfosceril palmitate, colistin, zinc eyewash F,corticorelin, corticotrophin, cortisone, cresol, croconazole,cromoglicic acid, crotamiton, cryofluorane, coumarin, cyanamide,cyanocobalamin, cyclizine, cyclobutyrol, cyclopentolate,cyclophosphamide, cycloserine, cyproheptadine, cyproterone, cysteine,cytarabine, cytarabine,2,4-dichlorobenzyl alcohol, 2-diethylaminoethanol, dacarbazine,daclizumab, dactinomycin, dalfopristin, dalteparin, danaparoid, danazol,dantrolene, dapiprazole, dapsone, darbepoetin alfa, darifenacin,Daunorubicin, deanol, deanolace, decarbazine, dectaflur F, deferiprone,deferoxamine, delapril, demeclocycline, denaverine, depreotide,dequalinium, desflurane, desipramine, desirudin, deslanoside,desloratadine, desmeninol, desmopressin, desogestrel, desoximetasone,deoxyribonuclease, detajmium, dexamethasone, dexchlorpheniramine,dexibuprofen, dexketoprofen, dexrazoxane, dextran, dextromethorphan,diacerein, diacetyl morphine, dibenzepin, diboterminalfa, diclofenac,diclofenamide, didanosine, dienestrol, dienogest, diethylstilbestrol,difloxacin, diflucortolone, diflunisal, digitoxin, digoxin,dihydralazine, dihydroergocornine, dihydroergocristine,dihydroergocryptine, dihydroergotamine, dihydroergotoxine,dihydrotachysterol, diisopropylamine, dipotassium clorazepate,diltiazem, dimenhydrinate, dimepranol, dimercaprol, dimethyl sulfoxide,dimethindene, disodium selenite, dinoprost, dinoprostone, diosmin,diphenhydramine, diphenoxylate, diphenylpyraline, dipivefrine,diprophylline, dipyridamole, disopyramide, dinitrogen monoxide,distigmine, disulfuram, dithranol, dixyrazine, D-norpseudoephedrine,dobesilate calcium, dobutamine, docetaxel, dofetilide, dolasetron,domperidone, donepezil, dopamine, dopexamine, dornase alfa, dorzolamide,dosulepin, doxapram, doxazosin, doxepin, doxorubicin, doxycycline,doxylamine, drofenine, droperidol, drospirenone, drotrecogin alfa,duloxetine, dutasteride, dydrogesterone, N,N′-dihydroxymethyl urea,ebastine, econazole, ecothiopate iodide, efalizumab, efavirenz,eflornithine, iron(III) ammonium citrate F, superparamagnetic ironoxide, elcatonin, eletriptan, emedastine, emepronium, emeproniumcarrageenate, emetine, emtricitabine, enalapril, enalaprilat, enflurane,enfuvirtide, enoxacin, enoxaparin, entacapone, ephedrine, ephedrineracephedrine, epinastine, epinephrine, epirubicin, eplerenone, epoetinalfa, epoetin beta, epoetin delta, epoprostenol, eprazinone, eprosartan,eptacog alfa, eptifibatide, eptotermin alfa, erdosteine, ergocalciferol,ergometrine, ergotamide, ertapenem, erythromycin, escitalopram, esmolol,esomeprazole, estradiol, estramustine, estriol, estrone, etacrynic acid,etamivan, etanercept, ethacridine, ethambutol, ethaverine,ethinylestradiol, ethisterone, ethosuximide, etidronic acid, etilefrine,etodolac, etofenamate, etofibrate, etofylline, etomidate, etonogestrel,etoposide, etoricoxib, everolimus, exametazime, exemestane, ezetimibe,3-fluorotyrosine, famciclovir, famotidine, felbamate, felbinac,felodipine, fenbufene, fendiline, fenofibrate, fenoterol, fenticonazole,fexofenadine, fibrinogen, fibrinolysin, filgrastim, finasteride,flavoxate, flecamide, flucloxacillin, fluconazole, fludarabine,fludeoxyglucose [¹⁸F], fludrocortisone, flufenamic acid, flumazenil,flumetasone, flunarizine, flunisolide, fluocinolone acetonide,fluocinonide, fluocortolone, fluophenozine, fluorescein dilaurate,fluorescein sodium, fluorometholone, fluorouracil, fluorophosphoricacid, fluorosilane, fluoxetil, fluoxetine, flupentixol, fluphenazine,flupirtine, fluprednidene, flurbiprofen, flutamide, fluticasone,flutrimazole, fluvastatin, fluvoxamine, folic acid, follitropin alfa,follitropin beta, folic acid, fomepizole, fomivirsen, fondaparinux,formestane, formoterol, fosamprenavir, foscarnet, fosfestrol,fosfomycin, fosinopril, fosphenyloin, fotemustine, framycetin,framycetin, frovatriptan, fulvestrant, furosemide, fusafungine, fusidicacid, fytic acid,gabapentin, gadobenic acid, gadobutrol, gadodiamide, gadopentetic acid,gadoteridol, gadoteric acid, gadoteric acid-meglumine, gadoxetic acid,galantamine, gallopamil, ganciclovir, ganirelix, gatifloxacin,gemcitabine, gemfibrozil, gentamicin, gepefrine, gestodene, glatiramer,glibenclamide, glibornuride, gliclazide, glimepiride, glipizide,gliquidone, glisoxepide, glucagon, glutamine, glutamic acid,glycopyrronium, glycopyrronium bromide, glycyrrhetinic acid,gonadorelin, goserelin, gramicidin, granisetron, grepafloxacin,griseofulvin, g-strophanthin, guajacol, guanethidine, guanfacine,¹³C urea, 4-hydroxybutyric acid, halcinonide, halofantrine,halometasone, haloperidol, halothane, haem, haematoporphyrin, heparin,hepatitis B vaccine, heptaminol, hexobarbital, hexobendine,hexoprenaline, histamine, histidine, homatropine, homofenazine, humanalbumin, hyaluronidase, hydralazine, hydrastinine, hydroquinone,hydrochlorothiazide, hydrocortisone, hydrotalcite F, hydroxocobalamin,hydroxycarbamide, hydroxychloroquine, hydroxycine, hydroxylamine,hydroxyprogesterone, hydroxyzine, hymecromone,ibandronic acid, ibopamine, ibritumomab tiuxetan, ibuprofen, ibutilide,idarubicin, ifosfamide, iloprost, imatinib, imatinib mesylate,imidapril, imiglucerase, imipenem, imipramine, imiquimod, immunocyanin,indanazoline, indapamide, indinavir, indium chloride [¹¹¹In], indobufen,indometacin, indoramin, infliximab, inosine, insulin, insulin aspart,insulin detemir, insulin glargine, insulin glulisine, insulin lispro,interferon alfa, interferon alfa-2 b), interferon alfacon-1, interferonbeta, interferon beta-1a), interferon beta-1b), interferon gamma,iobitridol, iodine, iodamide, iodixanol, ioflupane [¹²³I], iohexyl,iomeprol, iopamidol, iopentol, iopromide, iosarcol, iotrolan, iotroxicacid, ioversol, ioxaglic acid, ioxitalamic acid, ipatropium, irbesartan,irinotecan, irinotecan, isepamicin, isoaminile, isoconazole, isoflurane,isoleucine, isoniazid, isonicotinic acid, isoprenaline, isosorbide,isospaglumic acid, isotretinoin, isoxsuprine, isradipine, itraconazole,josamycin,potassium permanganate, kallidinogenase, kanamycin, kawain, kebuzone,ketamine, ketoconazole, ketoprofen, ketorolac, ketotifen, collagenase,creosote,labetalol, lacidipine, lactitol, lamivudine, lamotrigine, lanreotide,lansoprazole, laronidase, latanoprost, leflunomide, lenograstim,lepirudin, lercanidipine, letrozole, leucine, leuprorelin, levallorphan,levamisole, levetiracetam, levobunolol, levobupivacaine, levocabastine,levocetirizine, levodopa, levofloxacin, levofolinate calcium,levomepromazine, levomethadyl, levonorgestrel, levopropylhexedrine,levosimendan, levothyroxine, lidocaine, lincomycin, lindane, linezolid,liothyronine, lisinopril, lisuride, lobeline, lodoxamide, lofepramine,lomefloxacin, lomustine, lonazolac, loperamide, lopinavir, loratadine,lorazepam oxide, lornoxicam, losartan, loteprednole, lovastatin,lumefantrine, lutropin alfa, lymecycline, lynestrenol, lypressin,lysine,magaldrate F, magnesium pidolate, magnesium L-aspartate, mangafodipir,manidipine, maprotiline, mebendazole, mebeverine, meclofenoxate,mecloxamine, meclozine, medrogestone, medroxyprogesterone, mefenamicacid, mefloquine, megestrol, melagatrane, melitracen, melperol,melperone, melphalan, memantine, menadione, mepacrine, mepartricin,mephenyloin, mepindolol, mepivacaine, mepyramine, mequinol,mercaptamine, mercaptopurine, meropenem, mesalazine, mesna, mesterolone,mesuximide, metaclazepam, metamizole, metamphetamine, metenolone,metenolone acetate, metformin, methanthelinium, methazolamide,methenamine, methionine, methohexital, methotrexate, 5-methoxypsoralen,8-methoxypsoralen, methyl 5-aminolevulinate, methylbenactyzium bromide,methyldopa, methylergometrine, methylprednisolone, methylrosanilinium,methyltestosterone, methylthionium chloride, methysergide, metildigoxin,metipranolol, metoclopramide, metoprolol, methixene, metronidazole,mexiletine, mezlocillin, mianserine, miconazole, midodrine,mifepristone, miglitol, miglustat, milnacipran, milrinone, miltefosine,minocycline, minoxidil, mirtazapine, misoprostol, mitobronitol,mitomycin, mitotane, mitoxantrone, mivacurium chloride, mivacuronium,mizolastine, moclobemide, moexipril, molgramostim, molsidomine,mometasone, monochloroacetic acid, montelukast, moroctocog alfa,moxaverine, moxifloxacin, moxonidine, mupirocin, mycophenolate mofetil,nadifloxacin, nadrolon decanonate, nadroparin calcium, naftidrofuryl,naftifine, nalbuphine, nalide, nalmefene, nalmexone, naloxone,naltrexone, naluphine, naphazoline, 2-naphthol, naproxen, naratriptan,naratriptan, nateglinide, sodium aurothiomalate, sodium phenylbutyrate,sodium fluoride, sodium hyaluronate, sodium iodide [¹³¹I], sodiummolybdate [⁹⁹Mo], sodium phenylbutyrate, n-butyl-p-aminobenzoate,N-butylscopolaminium bromide, nebivolol, nedocromil, nefazodone,nefopam, nelfinavir, neomycin, neostigmine, neostigmine methylsulfate,netilmicin, nevirapine, n-heptyl-2-phenyl glycinate, nicardipine,nicergoline, nicethamide, niclosamine, nicoboxil, nicorandil, nicotine,nicotine aldehyde, nicotinamide, nicotine resinate, nicotinic acid,nicotinic acid ester, nicotinyl alcohol, nifedipine, niflumic acid,nifuratel, nilvadipine, nimesulide, nimodipine, nimorazole, nimustine,nisoldipine, nitisinone, nitrendipine, nitric oxide, nitrofurantoin,nitroglycerine, nizatidine, N-methylephedrine, nonacog alfa, nonivamide,noradrenalin, norelgestromin, norepinephrine, norethisterone,norfenefrine, norfloxacin, norgestimate, norgestrel, nortriptyline,noscapine, nystatin,obidoxime chloride, octafluoropropane, octocog alfa, octodrine,octreotide, odansetron, ofloxacin, olaflur F, olanzapine, olmesartanmedoxomil, olopatadine, olsalazine, omeprazole, omoconazole,ondansetron, opipramol, oral cholera vaccine, orciprenaline, orlistat,ornipressin, orphenadrine, oseltamivir, osteogenic protein-1: BMP-7,oxaprozin, oxatomide, oxcarbazepine, oxedrine tartrate, oxetacaine,oxiconazole, oxilofrine, oxitropium, 2-oxo-3-methylbutyric acid,2-oxo-3-methylvaleric acid, 2-oxo-3-phenylpropionic acid,2-oxo-4-methylvaleric acid, oxprenolol, oxybuprocaine, oxybuprocaine,oxybutynin, oxybutynin, oxyfedrine, oxymetazoline, oxytetracycline,oxytocin,paclitaxel, palinavir, palivizumab, palonosetrone, pamidronic acid,pancuronium, pantoprazole, papaverine, paracetamol, paraldehyde,parecoxib, paricalcitol, parnaparin, paromomycin, paroxetine,pefloxacin, pegfilgrastim, peginterferon alfa, pegvisomant, pemetrexed,penbutolol, penciclovir, penfluridol, penicillamine, benperidol,pentaerithrityl tetranitrate, pentamidine, pentetrazol, pentetreotide,pentosan polysulfate sodium, pentoxifylline, pentoxyverine, perazine,perchloric acid, perflenapent, perflisopent, perflutren, pergolide,perindopril, perphenazine, phenacetin, phenamazid, phenazone,phenazopyridine, pheniramine, phenol, phenolphthalein, phenoxybenzamine,phenoxymethylpenicillin, phenprocoumon, phentolamine, phenylalanine,phenylbutazone, phenylephrine, phenylpropanolamine, phenyltoloxamine,phenyloin, phloroglucinol, pholedrine, phthalylsulfathiazole,physostigmine, phytomenadione, phytosterol, picric acid, pilocarpine,pimecrolimus, pimozide, pinaverium bromide, pindolol, pioglitazone,pipamperone, pipazetate, pipecuronium bromide, pipemidic acid,pipenzolate, piperacillin, piprinhydrinate, piracetam, pirarubicin,pirbuterol, pirenzepine, piritramide, piroxicam, pivmecillinam,pizotifen, podophyllotoxin, polidocanol, polycarbophil, polyestradiolphosphate, polymyxin B, polymyxin-B, polystyrenesulfonic acid, porfimer,prajmaline, prajmalium bitartrate, pramipexole, pranoprofen, prasterone,pravastatin, prazepam, prazosin, prednicarbate, prednisolone,prednisone, pregabalin, proglumetacin, pridinol, prilocalne, primaquine,primidone, prithipendyl, procaine, procainamide, procarbazil,procarbazine, procyclidin, progesterone, proglumetacin, proglumide,proguanil, proline, promethazine, propacetamol, propafenon, propanolol,propicillin, propiverine, propofol, propranolol, propylthiouracil,propyphenazone, protamine, protamine sulfate, protein C, prothipendyl,prothrombin, protionamide, protirelin, proxymetacaine, proxyphylline,pseudoephedrine, Pulmonal, pyrantel, pyrazinamide, pyridostigmine,pyridostigmine bromide, pyridoxine, 3-pyridylmethanol, pyrimethamine,pyrithione zinc, pyritinol, pyrogallol, pyrvinium, pyrvinium embonate,mercury amide chloride, quetiapine, quinagolide, quinapril,quinupristin,rabeprazole, racephedrine, racecadotrile, raloxifene, raltitrexed,ramipril, ranitidine, rasagiline, rasburicase, raubasine, reboxetine,repaglinide, reproterol, reserpine, resorcinol, reteplase, retinol,reviparin, ribavirin, riboflavin, rifabutin, rifampicin, rifamycin,rifaximin, rilmenidine, riluzole, rimexolone, risedronic acid,risperidone, ritonavir, rituximab, rivastigmine, rizatriptan, rocuroniumbromide, rofecoxib, ropinirole, ropivacaine, ropivacaine, rosiglitazone,red mercuric sulfide F, roxatidine, roxithromycin,salbutamol, salicylic acid, salmeterol, nitric acid, nitrous acid,salverine, samarium [¹⁵³Sm] lexidronam, saquinavir, sulfur hexafluoride,scopolamine, selegiline, selenium sulfide, serine, sermorelin,sertaconazole, sertindole, sertraline, sevelamer, sevoflurane,sibutramine, silver chloride F, sildenafil, silibinin, simvastatin,sirolimus, formaldehyde solution, solifenacine, somatostatin,somatropin, sotalol, spaglumic acid, sparteine, spectinomycin,spiramycin, spirapril, spironolactone, stavudine, streptodornase,streptokinase, streptomycin, strontium ranelate, strontium chloride,strychnine, sucralfate F, sulbactam, sulesomab, sulfacetamide,sulfadiazine, sulfadimethoxine, sulfaguanidine, sulfamerazine,sulfamethoxazole, sulfamethoxydiazine, sulfametrole, sulfanilamide,sulfasalazine, sulfathiazole, sulfisomidine, sulindac, sulodexide,sulfur hexafluoride, sulpiride, sulprostone, sultamicillin, sultiame,sumatriptan, suxamethonium,tacalcitol, tacrolimus, tadalafil, tamoxifen, tamsulosin, tasonermin,taurolidine, tazarotene, tazobactam, tegafur, teicoplanin,telithromycin, telmisartan, temoporfin, temozolomide, tenecteplase,teniposide, tenofovir, tenofovir disoproxil, tenoxicam, terazosin,terbinafine, terbutaline, terfenadine, teriparatide, terizidone,terlipressin, testosterone, testosterone propionate, testosteroneundecanoate, tetracaine, tetracosactide, tetracycline,tetrafluoroborate-1+, tetrofosmin, tetryzoline, thallium chloride[²⁰¹Tl], theobromine, theodrenaline, theodrenaline, theophylline,thiamazole, thiamine, thiethylperazine, thiocolchicoside, thiopental,thioridazine, thiotepa, threonine, thrombin, thrombokinase, thymol,thyrotropin alfa, tiagabine, tianeptine, tiapride, tibolone,ticlopidine, tiludronic acid, timolol, tinzaparin, tioconazole,tioguanine, tiotropium bromide, tirilazad, tirofiban, tisopurine,tizamidine, tizanidine, tobramycin, tocamide, tolazoline, tolbutamide,tolcapone, tolfenamic acid, tolmetin, tolperisone, tolterodine,topiramate, topotecan, torasemide, toremifene, tramazoline,trandolapril, tranexamic acid, tranylcypromine, trapidil, trastuzumab,travoprost, trazodone, tretinoin, triamcinolone, triamcinoloneacetonide, triamterene, trichloroacetic acid, triethylperazine,trifluoperazine, triflupromazine, trihexyphenidyl, trimebutine,trimecaine, trimegestone, trimetazidine, trimethoprim, trimipramine,tripelennamine, triprolidine, triptorelin, tritoqualine, trofosfamide,tromantadine, trometamol, tropicamide, tropisetron, trospium,tryptophan, tubocurarine chloride, tulobuterol, tyloxapol, tyrosine,tyrothricin,unoprostone, urapid, urapidil, urokinase, ursodeoxycholic acid,valaciclovir, valdecoxib, valganciclovir, valine, valproic acid,valsartan, vancomycin, vardenafil, vecuronium, vecuronium bromide,venlafaxine, verapamil, verteporfin, vigabatrin, viloxazine,vinblastine, vincamine, vincristine, vindesine, vinorelbine,vinpocetine, viquidil, voriconazole, votumumab,hydrogen peroxide,xantinol nicotinate, ximelagatrane, xipamide, xylometazoline,yohimbine, yttrium ⁹⁰Y chloride,zalcitabine, zaleplon, zanamivir, zidovudine, zinc acetate dihydrate,zinc chloride, zinc citrate, zinc sulfate, ziprasidone, zofenopril,zoledronic acid, zolmitriptan, zolpidem, zolpidem tartrate, zonisamide,zopiclone, zotepine, zucklopantexol, and zuclopenthixol.

The above-stated compounds are predominantly stated by theirinternational nonproprietary name (INN) and are known to the personskilled in the art. Further details may be found, for example, byreferring to International Nonproprietary Names (INN) for PharmaceuticalSubstances, World Health Organization (WHO).

In a preferred embodiment, the pharmaceutical dosage form is monolithic.

The pharmaceutical dosage form according to the invention ischaracterized by a comparatively homogeneous distribution of thepharmacologically active compound (A). Preferably, the content of thepharmacologically active compound (A) in two segments of thepharmaceutical dosage form having a volume of 1.0 mm³ each, deviatesfrom one another by not more than ±10%, more preferably not more thanmore than ±7.5%, still more preferably not more than ±5.0%, mostpreferably not more than ±2.5%, and in particular not more than ±1.0%.When the pharmaceutical dosage form is film coated, said two segments ofthe pharmaceutical dosage form having a volume of 1.0 mm³ each arepreferably segments of the core, i.e. do not contain any coatingmaterial.

Preferably, all components of the pharmaceutical dosage form accordingto the invention have a comparatively homogeneous distribution withinthe pharmaceutical dosage form. Preferably, the content of eachcomponent in two segments of the pharmaceutical dosage form having avolume of 1.0 mm³ each, deviates from one another by not more than ±10%,more preferably not more than more than ±7.5%, still more preferably notmore than ±5.0%, most preferably not more than ±2.5%, and in particularnot more than ±1.0%. When the pharmaceutical dosage form is film coated,said two segments of the pharmaceutical dosage form having a volume of1.0 mm³ each are preferably segments of the core, i.e. do not containany coating material.

Preferably, the pharmaceutical dosage form according to the invention isadapted for oral administration. It is also possible, however, toadminister the pharmaceutical dosage form via different routes and thus,the pharmaceutical dosage form may alternatively be adapted for buccal,lingual, rectal or vaginal administration. Implants are also possible.

In a preferred embodiment, the pharmaceutical dosage form according tothe invention is adapted for administration once daily. In anotherpreferred embodiment, the pharmaceutical dosage form according to theinvention is adapted for administration twice daily. In still anotherpreferred embodiment, the pharmaceutical dosage form according to theinvention is adapted for administration thrice daily.

For the purpose of the specification, “twice daily” means equal timeintervals, i.e., every 12 hours, or different time intervals, e.g., 8and 16 hours or 10 and 14 hours, between the individual administrations.

For the purpose of the specification, “thrice daily” means equal timeintervals, i.e., every 8 hours, or different time intervals, e.g., 6, 6and 12 hours; or 7, 7 and 10 hours, between the individualadministrations.

Preferably, the pharmaceutical dosage form according to the inventioneffects an at least partially delayed release of the pharmacologicallyactive compounds (A).

Delayed release is understood according to the invention preferably tomean a release profile in which the pharmacologically active compound(A) is released over a relatively long period with reduced intakefrequency with the purpose of extended therapeutic action. This isachieved in particular with peroral administration. The expression “atleast partially delayed release” covers according to the invention anypharmaceutical dosage forms which ensure modified release of thepharmacologically active compounds (A) contained therein. Thepharmaceutical dosage forms preferably comprise coated or uncoatedpharmaceutical dosage forms, which are produced with specific auxiliarysubstances, by particular processes or by a combination of the twopossible options in order purposefully to change the release rate orlocation of release.

In the case of the pharmaceutical dosage forms according to theinvention, the release time profile may be modified e.g. as follows:extended release, repeat action release, prolonged release and sustainedrelease.

For the purpose of the specification “extended release” preferably meansa product in which the release of active compound is delayed for afinite lag time, after which release is unhindered. For the purpose ofthe specification “repeat action release” preferably means a product inwhich a first portion of active compound is released initially, followedby at least one further portion of active compound being releasedsubsequently. For the purpose of the specification “prolonged release”preferably means a product in which the rate of release of activecompound from the formulation after administration has been reduced, inorder to maintain therapeutic activity, to reduce toxic effects, or forsome other therapeutic purpose. For the purpose of the specification“sustained release” preferably means a way of formulating a medicine sothat it is released into the body steadily, over a long period of time,thus reducing the dosing frequency. For further details, reference maybe made, for example, to K. H. Bauer, Lehrbuch der PharmazeutischenTechnologie, 6th edition, WVG Stuttgart, 1999; and EuropeanPharmacopoeia.

The pharmaceutical dosage form according to the invention may compriseone or more pharmacologically active compounds (A) at least in part in afurther delayed-release form, wherein delayed release may be achievedwith the assistance of conventional materials and processes known to theperson skilled in the art, for example by embedding the substance in adelayed-release matrix or by applying one or more delayed-releasecoatings. Substance release must, however, be controlled such thataddition of delayed-release materials does not impair the necessarybreaking strength. Controlled release from the pharmaceutical dosageform according to the invention is preferably achieved by embedding thesubstance in a matrix. Component (C) may serve as such a matrix. Theauxiliary substances acting as matrix materials control release. Matrixmaterials may, for example, be hydrophilic, gel-forming materials, fromwhich release proceeds mainly by diffusion, or hydrophobic materials,from which release proceeds mainly by diffusion from the pores in thematrix.

Preferably, the release profile is substantially matrix controlled,preferably by embedding component (A) in a matrix comprising component(C) and optionally, further matrix materials. Preferably, the releaseprofile is not osmotically driven. Preferably, release kinetics is notzero order.

Preferably, under physiological conditions the pharmaceutical dosageform according to the invention has released after 30 minutes 0.1 to75%, after 240 minutes 0.5 to 95%, after 480 minutes 1.0 to 100% andafter 720 minutes 2.5 to 100% of the pharmacologically active compound(A). Further preferred release profiles R₁ to R₅ are summarized in thetable here below [all data in wt.-% of released pharmacologically activecompound (A)]:

time R₁ R₂ R₃ R₄ R₅ 60 min 0-30 0-50 0-50 15-25 20-50 120 min 0-40 0-750-75 25-40 40-75 240 min 3-55 3-95 10-95  40-70 60-95 480 min 10-65 10-100 35-100 60-90  80-100 720 min 20-75  20-100 55-100  70-100  90-100960 min 30-88  30-100 70-100 >80 1440 min 50-100 50-100 >90 2160 min >80>80

Preferably, under in vitro conditions the pharmaceutical dosage form hasreleased after 0.5 h 1.0 to 35 wt.-%, after 1 h 5.0 to 45 wt.-%, after 2h 10 to 60 wt.-%, after 4 h at least 15 wt.-%, after 6 h at least 20wt.-%, after 8 h at least 25 wt.-% and after 12 h at least 30 wt.-% ofthe pharmacologically active compound (A) that was originally containedin the pharmaceutical dosage form.

Suitable in vitro conditions are known to the skilled artisan. In thisregard it can be referred to, e.g., the European Pharmacopoeia and tothe experimental section. Preferably, the release profile is measuredunder the following conditions: Paddle apparatus equipped with sinker,50 rpm, 37±5° C., 900 mL simulated intestinal fluid pH 6.8 (phosphatebuffer). In a preferred embodiment, to rotational speed of the paddle isincreased to 100 rpm.

Preferred release profiles R₆ to R₁₁ of the pharmacologically activecompound (A) contained in the pharmaceutical dosage form are summarizedin the following table:

[wt.-%] R₆ R₇ R₈ R₉ R₁₀ R₁₁ after 30 min 16.3 ± 7.5 16.3 ± 5.0 16.3 ±2.5 15.8 ± 7.5 15.8 ± 5.0 15.8 ± 2.5 after 60 min 27.5 ± 7.5 25.0 ± 5.025.0 ± 2.5 24.3 ± 7.5 24.3 ± 5.0 24.3 ± 2.5 after 90 min 32.1 ± 7.5 32.1± 5.0 32.1 ± 2.5 31.2 ± 7.5 31.2 ± 5.0 31.2 ± 2.5 after 120 min 38.2 ±7.5 38.2 ± 5.0 38.2 ± 2.5 37.4 ± 7.5 37.4 ± 5.0 37.4 ± 2.5 after 150 min43.4 ± 7.5 43.4 ± 5.0 43.4 ± 2.5 42.7 ± 7.5 42.7 ± 5.0 42.7 ± 2.5 after180 min 48.2 ± 7.5 48.2 ± 5.0 48.2 ± 2.5 47.6 ± 7.5 47.6 ± 5.0 47.6 ±2.5 after 210 min 52.7 ± 7.5 52.7 ± 5.0 52.7 ± 2.5 52.2 ± 7.5 52.2 ± 5.052.2 ± 2.5 after 240 min 56.8 ± 7.5 56.8 ± 5.0 56.8 ± 2.5 56.5 ± 7.556.5 ± 5.0 56.5 ± 2.5 after 270 min 60.7 ± 7.5 60.7 ± 5.0 60.7 ± 2.560.4 ± 7.5 60.4 ± 5.0 60.4 ± 2.5 after 300 min 64.5 ± 7.5 64.5 ± 5.064.5 ± 2.5 64.2 ± 7.5 64.2 ± 5.0 64.2 ± 2.5 after 330 min 67.9 ± 7.567.9 ± 5.0 67.9 ± 2.5 67.7 ± 7.5 67.7 ± 5.0 67.7 ± 2.5 after 360 min71.1 ± 7.5 71.1 ± 5.0 71.1 ± 2.5 71.0 ± 7.5 71.0 ± 5.0 71.0 ± 2.5 after390 min 74.2 ± 7.5 74.2 ± 5.0 74.2 ± 2.5 74.0 ± 7.5 74.0 ± 5.0 74.0 ±2.5 after 420 min 77.0 ± 7.5 77.0 ± 5.0 77.0 ± 2.5 76.9 ± 7.5 76.9 ± 5.076.9 ± 2.5 after 450 min 79.5 ± 7.5 79.5 ± 5.0 79.5 ± 2.5 79.5 ± 7.579.5 ± 5.0 79.5 ± 2.5 after 480 min 81.9 ± 7.5 81.9 ± 5.0 81.9 ± 2.582.0 ± 7.5 82.0 ± 5.0 82.0 ± 2.5 after 510 min 84.2 ± 7.5 84.2 ± 5.084.2 ± 2.5 84.2 ± 7.5 84.2 ± 5.0 84.2 ± 2.5 after 540 min 86.3 ± 7.586.3 ± 5.0 86.3 ± 2.5 86.3 ± 7.5 86.3 ± 5.0 86.3 ± 2.5 after 570 min88.3 ± 7.5 88.3 ± 5.0 88.3 ± 2.5 88.1 ± 7.5 88.1 ± 5.0 88.1 ± 2.5 after600 min 90.1 ± 7.5 90.1 ± 5.0 90.1 ± 2.5 89.8 ± 7.5 89.8 ± 5.0 89.8 ±2.5 after 630 min 91.9 ± 7.5 91.9 ± 5.0 91.9 ± 2.5 91.4 ± 7.5 91.4 ± 5.091.4 ± 2.5 after 660 min 93.3 ± 7.5 93.3 ± 5.0 93.3 ± 2.5 92.7 ± 7.592.7 ± 5.0 92.7 ± 2.5 after 690 min 94.3 ± 7.5 94.3 ± 5.0 94.3 ± 2.594.0 ± 7.5 94.0 ± 5.0 94.0 ± 2.5 after 720 min 95.8 ± 7.5 95.8 ± 5.095.8 ± 2.5 95.1 ± 7.5 95.1 ± 5.0 95.1 ± 2.5

Preferably, the release properties of the pharmaceutical dosage formaccording to the invention are substantially independent from the pHvalue of the release medium, i.e. preferably the release profile inartificial intestinal juice substantially corresponds to the releaseprofile in artificial gastric juice. Preferably, at any given time pointthe release profiles deviate from one another by not more than 20%, morepreferably not more than 15%, still more preferably not more than 10%,yet more preferably not more than 7.5%, most preferably not more than5.0% and in particular not more than 2.5%.

Preferably, the pharmaceutical dosage form according to the inventionexhibits a uniform release profile. Preferably, the release profile ofthe pharmacologically active compound (A) is interindividually uniform(i.e. when comparing pharmaceutical dosage forms obtained from the sameprocess) (c.f. FIG. 22) and/or uniform within a single pharmaceuticaldosage form (i.e. when comparing segments of the same pharmaceuticaldosage form). Preferably, when comparing two probes each having a massof preferably 500 mg, the total amount of the released active compoundfor any given time point of the measurement does not deviate by morethan 20%, more preferably not more than 15%, still more preferably notmore than 10%, yet more preferably not more than 7.5%, most preferablynot more than 5.0% and in particular not more than 2.5%.

Preferably, the entire outer surface of the dosage form, preferablytablet, according to the invention is permeable for water and forcomponent (A), i.e., preferably the water penetration characteristics ofthe surface are identical everywhere. This means that preferably, thedosage form, preferably tablet, is not partially coated with a materialhaving a barrier effect which would impede the penetration of water atthe location of the surface where it is applied.

Preferably, the release profile of the pharmaceutical dosage formaccording to the present invention is stable upon storage, preferablyupon storage at elevated temperature, e.g. 37° C., for 3 months insealed containers. In this regard “stable” means that when comparing theinitial release profile with the release profile after storage, at anygiven time point the release profiles deviate from one another by notmore than 20%, more preferably not more than 15%, still more preferablynot more than 10%, yet more preferably not more than 7.5%, mostpreferably not more than 5.0% and in particular not more than 2.5% (cf.FIG. 24).

It has been surprisingly found that by modifying the outer shape of thepharmaceutical dosage form the storage stability, e.g. the storagestability of the release profile, can be increased compared toconventional dosage forms having a comparable release profile beforestorage.

Preferably, the pharmaceutical dosage form according to the inventioncontains at least one polymer (C), for the purpose of the specificationalso referred to as “component (C)”. Preferably, the pharmaceuticaldosage form contains at least one synthetic, semi-synthetic or naturalpolymer (C), which contributes considerably to the elevated breakingstrength (resistance to crushing) of the pharmaceutical dosage form. Forthe purpose of the specification a “semi-synthetic” product has beenproduced by chemical manipulation of naturally occurring substances.

Preferably, the mechanical properties of the pharmaceutical dosage formaccording to the invention, particularly its breaking strength,substantially rely on the presence of polymer (C), although its merepresence does not suffice in order to achieve said properties. Theadvantageous properties of the pharmaceutical dosage form according tothe invention, in particular also its mechanical properties, may notautomatically be achieved by simply processing the pharmacologicallyactive compound (A), polymer (C), and optionally further excipients bymeans of conventional methods for the preparation of pharmaceuticaldosage forms. In fact, usually suitable apparatuses must be selected forthe preparation and critical processing parameters must be adjusted,particularly pressure/force, temperature and time. Thus, even ifconventional apparatuses are used, the process protocols usually must beadapted in order to meet the required criteria.

Preferably, polymer (C) is water-soluble. Preferably, polymer (C) issubstantially unbranched.

Polymer (C) may comprise a single type of polymer having a particularaverage molecular weight, or a mixture (blend) of different polymers,such as two, three, four or five polymers, e.g., polymers of the samechemical nature but different average molecular weight, polymers ofdifferent chemical nature but same average molecular weight, or polymersof different chemical nature as well as different molecular weight.

Individual or combinations of polymers may be selected from the groupcomprising polyalkylene oxide, preferably polymethylene oxide,polyethylene oxide, polypropylene oxide; polyethylene, polypropylene,polyvinyl chloride, polycarbonate, polystyrene, polyvinylpyrrolidone,poly(alk)acrylate, poly(hydroxy fatty acids), such as for examplepoly(3-hydroxybutyrate-co-3-hydroxyvalerate) (Biopol®),poly(hydroxyvaleric acid); polycaprolactone, polyvinyl alcohol,polyesteramide, polyethylene succinate, polylactone, polyglycolide,polyurethane, polyamide, polylactide, polyacetal (for examplepolysaccharides optionally with modified side chains),polylactide/glycolide, polylactone, polyglycolide, polyorthoester,polyanhydride, block polymers of polyethylene glycol and polybutyleneterephthalate (Polyactive®), polyanhydride (Polifeprosan), copolymersthereof, block-copolymers thereof, and mixtures of at least two of thestated polymers, or other polymers with the above characteristics.

Preferably, polymer (C) comprises a polyalkylene oxide, more preferablya polyethylene oxide, a polypropylene oxide, an ethylene oxide-propyleneoxide copolymerisate, which may be e.g. a random copolymer, alternatingcopolymer or block copolymer, or a mixture of any of the foregoing.

Particularly preferred are high molecular weight polymers with apreferably weight average molecular weight (M_(w)) or viscosity averagemolecular weight (M_(n)) of at least of at least 0.1·10⁶ g/mol, of atleast 0.2·10⁶ g/mol, of at least 0.5·10⁶ g/mol, of at least 1.0·10⁶g/mol, of at least 2.5·10⁶ g/mol, of at least 5.0·10⁶ g/mol, of at least7.5·10⁶ g/mol or of at least 10·10⁶ g/mol, preferably 1.0·10⁶ g/mol to15·10⁶ g/mol. Suitable methods for determining M_(w) or M_(η) are knownto the person skilled in the art. Preferably, M_(η) is determined usingrheological measurements and M_(w) is determined using gel permeationchromatography (GPC) on suitable phases.

Preferably, the molecular weight dispersity M_(w)/M_(n) of polymer (C)is within the range of 2.5±2.0, more preferably 2.5±1.5, still morepreferably 2.5±1.0, yet more preferably 2.5±0.8, most preferably2.5±0.6, and in particular 2.5±0.4.

The polymers preferably have a viscosity at 25° C. of 4,500 to 17,600cP, measured in a 5 wt.-% aqueous solution using a model RVF Brookfieldviscosimeter (spindle no. 2/rotational speed 2 rpm), of 400 to 4,000 cP,measured on a 2 wt.-% aqueous solution using the stated viscosimeter(spindle no. 1 or 3/rotational speed 10 rpm) or of 1,650 to 10,000 cP,measured on a 1 wt.-% aqueous solution using the stated viscosimeter(spindle no. 2/rotational speed 2 rpm).

Most preferred are thermoplastic polyalkylene oxides having a weightaverage molecular weight (M_(w)) or a viscosity average molecular weight(M_(η)) of at least 0.2·10⁶ g/mol, more preferably at least 0.3·10⁶g/mol, still more preferably at least 0.4·10⁶ g/mol, yet more preferablyat least 0.5·10⁶ g/mol, most preferably at least 1.0·10⁶ g/mol and inparticular within the range of 1.0·10⁶ to 15·10⁶ g/mol are preferred,e.g. polyethylene oxides, polypropylene oxides or the (block-)copolymersthereof.

In a preferred embodiment according to the invention the polymer (C)comprises

-   -   a polyalkylene oxide having a weight average molecular weight        (M_(w)) or viscosity average molecular weight (M_(η)) of at        least 0.2·10⁶ g/mol        in combination with    -   at least one further polymer, preferably but not necessarily        also having a weight average molecular weight (M_(w)) or        viscosity average molecular weight (M_(η)) of at least 0.2·10⁶        g/mol, selected from the group consisting of polyethylene,        polypropylene, polyvinyl chloride, polycarbonate, polystyrene,        polyacrylate, poly(hydroxy fatty acids), polycaprolactone,        polyvinyl alcohol, polyesteramide, polyethylene succinate,        polylactone, polyglycolide, polyurethane, polyvinylpyrrolidone,        polyamide, polylactide, polylactide/glycolide, polylactone,        polyglycolide, polyorthoester, polyanhydride, block polymers of        polyethylene glycol and polybutylene terephthalate,        polyanhydride, polyacetal, cellulose esters, cellulose ethers        and copolymers thereof. Cellulose esters and cellulose ethers        are particularly preferred, e.g. methylcellulose,        ethylcellulose, hydroxymethylcellulose,        hydroxypropylmethylcellulose, carboxymethylcellulose, and the        like.

In a preferred embodiment, said further polymer is neither apolyalkylene oxide nor a polyalkylene glycol. Nonetheless, thepharmaceutical dosage form may contain polyalkylene glycol, e.g. asplasticizer, but then, the pharmaceutical dosage form preferably is aternary mixture of polymers: component (C)+further polymer+plasticizer.

In a particularly preferred embodiment, said further polymer is ahydrophilic cellulose ester or cellulose ether, preferablyhydroxypropylmethylcellulose, preferably having an average viscosity of100,000±50,000 mPas, more preferably 100,000±20,000 mPas.

Preferably, the content of said further polymer amounts to 0.5 to 25wt.-%, more preferably 1.0 to 20 wt.-%, still more preferably 2.0 to17.5 wt.-%, yet more preferably 3.0 to 15 wt.-% and most preferably 4.0to 12.5 wt.-% and in particular 5.0 to 10 wt.-%, based on the totalweight of the polyalkylene oxide.

In a preferred embodiment the relative weight ratio of said polyalkyleneoxide and said further polymer is within the range of from 20:1 to 1:20,more preferably 10:1 to 1:10, still more preferably 7:1 to 1:5, yet morepreferably 5:1 to 1:1, most preferably 4:1 to 1, 5:1 and in particular3:1 to 2:1.

Preferably, the content of said further polymer amounts to 0.5 to 25wt.-%, more preferably 1.0 to 20 wt.-%, still more preferably 2.0 to22.5 wt.-%, yet more preferably 3.0 to 20 wt.-% and most preferably 4.0to 17.5 wt.-% and in particular 5.0 to 15 wt.-%, based on the totalweight of the pharmaceutical dosage form.

It is not intended to be bound by any theory, but it is believed thatthe further polymer may serve as a supplementary matrix material thatguarantees a minimal retardant effect on the release of thepharmacologically active compound (A) even if the molecular chains ofthe polyalkylene oxide have been partially damaged in the course of themanufacture of the pharmaceutical dosage form, e.g. by extrusion,thereby decreasing the average molecular weight. Furthermore, it seemsthat the further polymer contributes to the storage stability of thedosage form, particularly with respect to its release profile.

Physiologically acceptable, hydrophobic materials which are known to theperson skilled in the art may be used as supplementary matrix materials.Polymers, particularly preferably cellulose ethers, cellulose estersand/or acrylic resins are preferably used as hydrophilic matrixmaterials. Ethylcellulose, hydroxypropylmethylcellulose,hydroxypropylcellulose, hydroxymethylcellulose, poly(meth)acrylic acidand/or the derivatives thereof, such as the salts, amides or estersthereof are very particularly preferably used as matrix materials.Matrix materials prepared from hydrophobic materials, such ashydrophobic polymers, waxes, fats, long-chain fatty acids, fattyalcohols or corresponding esters or ethers or mixtures thereof are alsopreferred. Mono- or diglycerides of C12-C30 fatty acids and/or C12-C30fatty alcohols and/or waxes or mixtures thereof are particularlypreferably used as hydrophobic materials. It is also possible to usemixtures of the above-stated hydrophilic and hydrophobic materials asmatrix materials.

Preferably, the overall content of polymer (C) is preferably at least 5wt.-%, at least 10 wt.-%, at least 15 wt.-% or at least 20 wt.-%, morepreferably at least 30 wt.-%, still more preferably at least 40 wt.-%,most preferably at least 50 wt.-% and in particular at least 60 wt.-%,of the total weight of the pharmaceutical dosage form. In a preferredembodiment the content of the polymer (C) is within the range of fromabout 20 to about 49 wt.-% of the total weight of the pharmaceuticaldosage form.

In a preferred embodiment, the overall content of polymer (C) is withinthe range of 25±20 wt.-%, more preferably 25±15 wt.-%, most preferably25±10 wt.-%, and in particular 25±5 wt.-%. In another preferredembodiment, the overall content of polymer (C) is within the range of35±20 wt.-%, more preferably 35±15 wt.-%, most preferably 35±10 wt.-%,and in particular 35±5 wt.-%. In still another preferred embodiment, theoverall content of polymer (C) is within the range of 45±20 wt.-%, morepreferably 45±15 wt.-%, most preferably 45±10 wt.-%, and in particular45±5 wt.-%. In yet another preferred embodiment, the overall content ofpolymer (C) is within the range of 55±20 wt.-%, more preferably 55±15wt.-%, most preferably 55±10 wt.-%, and in particular 55±5 wt.-%. In afurther preferred embodiment, the overall content of polymer (C) iswithin the range of 65±20 wt.-%, more preferably 65±15 wt.-%, mostpreferably 65±10 wt.-%, and in particular 65±5 wt.-%. In still a furthera preferred embodiment, the overall content of polymer (C) is within therange of 75±20 wt.-%, more preferably 75±15 wt.-%, most preferably 75±10wt.-%, and in particular 75±5 wt.-%.

In a preferred embodiment, polymer (C) is homogeneously distributed inthe pharmaceutical dosage form according to the invention. Preferably,polymer (C) forms a matrix in which the pharmacologically activecompound (A) is embedded. In a particularly preferred embodiment, thepharmacologically active compound (A) and polymer (C) are intimatelyhomogeneously distributed in the pharmaceutical dosage form so that thepharmaceutical dosage form does not contain any segments where eitherpharmacologically active compound (A) is present in the absence ofpolymer (C) or where polymer (C) is present in the absence ofpharmacologically active compound (A).

When the pharmaceutical dosage form is film coated, the polymer (C) ispreferably homogeneously distributed in the core of the pharmaceuticaldosage form, i.e. the film coating preferably does not contain polymer(C). Nonetheless, the film coating as such may of course contain one ormore polymers, which however, preferably differ from the polymer (C)contained in the core.

Preferably, the pharmaceutical dosage form according to the inventioncontains a coating, preferably a film-coating. Suitable coatingmaterials are known to the skilled person. Suitable coating materialsare commercially available, e.g. under the trademarks Opadry® andEudragit®.

Examples of suitable materials include cellulose esters and celluloseethers, such as methylcellulose (MC), hydroxypropylmethylcellulose(HPMC), hydroxypropylcellulose (HPC), hydroxyethylcellulose (HEC),sodium carboxymethylcellulose (Na-CMC), ethylcellulose (EC), celluloseacetate phthalate (CAP), hydroxypropylmethylcellulose phthalate (HPMCP);poly(meth)acrylates, such as aminoalkylmethacrylate copolymers,ethylacrylate methylmethacrylate copolymers, methacrylic acidmethylmethacrylate copolymers, methacrylic acid methylmethacrylatecopolymers; vinyl polymers, such as polyvinylpyrrolidone,polyvinylacetatephthalate, polyvinyl alcohol, polyvinylacetate; andnatural film formers, such as shellack.

In a particularly preferred embodiment, the coating is water-soluble.Preferably, the coating is based on polyvinyl alcohol, such as polyvinylalcohol-part. hydrolyzed, and may additionally contain polyethyleneglycol, such as macrogol 3350, and/or pigments.

The coating of the pharmaceutical dosage form can increase its storagestability.

The coating can be resistant to gastric juices and dissolve as afunction of the pH value of the release environment. By means of thiscoating, it is possible to ensure that the pharmaceutical dosage formaccording to the invention passes through the stomach undissolved andthe active compound is only released in the intestines. The coatingwhich is resistant to gastric juices preferably dissolves at a pH valueof between 5 and 7.5.

Corresponding materials and methods for the delayed release of activecompounds and for the application of coatings which are resistant togastric juices are known to the person skilled in the art, for examplefrom “Coated Pharmaceutical dosage forms—Fundamentals, ManufacturingTechniques, Biopharmaceutical Aspects, Test Methods and Raw Materials”by Kurt H. Bauer, K. Lehmann, Hermann P. Osterwald, Rothgang, Gerhart,1st edition, 1998, Medpharm Scientific Publishers.

It has been surprisingly found that the pharmaceutical dosage forms canbe easily film coated, although the outer shape of the pharmaceuticaldosage forms may deviate from conventional shapes of dosage forms. Forexample, when the pharmaceutical dosage forms according to the inventionare shaped by means of an H-plunger, a skilled person would expect thatsubstantial stapling or stacking and pair formation occurs when sprayingthe coating material on the dosage form in suitable devices. Suchstacking and agglomeration of the dosage form would deteriorate thecoating performance and hence, the film quality. However, it has beensurprisingly found that even pharmaceutical dosage forms havingirregular shapes may be smoothly coated.

In a particularly preferred embodiment,

-   -   the pharmaceutical dosage form is thermoformed, preferably by        extrusion; and/or    -   a portion of the surface of the pharmaceutical dosage form is        convex, another portion of its surface is concave; and/or    -   the pharmacologically active compound (A) is a psychotropically        acting substance, preferably an analgesic, more preferably a        drug selected from the group consisting of opioids, stimulants,        tranquillisers (e.g. barbiturates and benzodiazepines) and other        narcotics; and/or    -   the content of the pharmacologically active compound (A) is at        least 0.5 wt.-%, based on the total weight of the dosage form;        and/or    -   polymer (C) is an polyalkylene oxide having a weight average        molecular weight of at least 200,000 g/mol, preferably at least        500,000 g/mol, more preferably within the range of from        1,000,000 to 10,000,000 g/mol; and/or    -   the content of the polyalkylene oxide is at least 15 wt.-%,        based on the total weight of the dosage form; and/or    -   the opioid is embedded in the polyalkylene oxide, i.e., in a        matrix formed by the polyalkylene oxide; and/or    -   the pharmaceutical dosage form contains a plasticizer,        preferably polyethylene glycol; and/or    -   the content of said plasticizer is at least 5 wt.-%, based on        the total weight of the dosage form; and/or    -   besides polymer (C), the pharmaceutical dosage form contains a        further polymer selected from the group consisting of cellulose        ethers, cellulose esters and acrylates, preferably HPMC; and/or    -   the content of said further polymer is at least 1 wt.-%, based        on the total weight of the dosage form; and/or    -   the pharmaceutical dosage form contains an antioxidant,        preferably α-tocopherol; and/or    -   the content of said antioxidant is at least 0.05 wt.-%, based on        the total weight of the dosage form; and/or    -   the pharmaceutical dosage form is adapted for oral        administration once daily or twice daily; and/or    -   the pharmaceutical dosage form contains a coating, preferably a        film-coating.

Besides the pharmacologically active compound (A) and polymer (C) thepharmaceutical dosage form according to the invention may containfurther constituents, such as conventional pharmaceutical excipients.

In a preferred embodiment, the pharmaceutical dosage form contains atleast one natural, semi-synthetic or synthetic wax (D), for the purposeof the specification also referred to as “component (D)”. Preferredwaxes are those with a softening point of at least 50° C., morepreferably of at least 55° C., still more preferably of at least 60° C.,most preferably of at least 65° C. and in particular at least 70° C.

Carnauba wax and beeswax are particularly preferred. Carnauba wax isvery particularly preferred. Carnauba wax is a natural wax which isobtained from the leaves of the carnauba palm and has a softening pointof at least 80° C. When the wax component is additionally contained, itscontent is sufficiently high so that the desired mechanical propertiesof the pharmaceutical dosage form are achieved.

Auxiliary substances (B), further purpose of the specification alsoreferred to as “component (B)”, which may be contained in thepharmaceutical dosage form according to the invention are those knownauxiliary substances which are conventional for the formulation of solidpharmaceutical dosage forms.

Examples of auxiliary substances (B) are plasticizers, (further) matrixmaterials, antioxidants and the like.

Suitable plasticizers include triacetin and polyethylene glycol,preferably a low molecular weight polyethylene glycol (e.g. macrogol6000).

Matrix materials are auxiliary substances which influence activecompound release, preferably hydrophobic or hydrophilic, preferablyhydrophilic polymers, very particularly preferablyhydroxypropylmethylcellulose, and/or antioxidants. Polymers,particularly preferably cellulose ethers, cellulose esters and/oracrylic resins are preferably contained as hydrophilic matrix materials.Ethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose,hydroxymethylcellulose, poly(meth)acrylic acid and/or the derivativesthereof, such as the copolymers, salts, amides or esters thereof arevery particularly preferably contained as matrix materials.

Suitable antioxidants are ascorbic acid, butylhydroxyanisole (BHA),butylhydroxytoluene (BHT), salts of ascorbic acid, monothioglycerol,phosphorous acid, vitamin C, vitamin E and the derivatives thereof,coniferyl benzoate, nordihydroguajaretic acid, gallus acid esters,sodium bisulfite, particularly preferably butylhydroxytoluene orbutylhydroxyanisole and α-tocopherol. The antioxidant is preferably usedin quantities of 0.01 to 10 wt.-%, preferably of 0.03 to 5 wt.-%,relative to the total weight of the pharmaceutical dosage form.

Preferred compositions X₁ to X₄ of the pharmaceutical dosage formaccording to the invention are summarized in the table here below:

wt.-% X₁ X₂ X₃ X₄ component (A) 26.5 ± 25 26.5 ± 20 26.5 ± 15 26.5 ± 13polyalkylene oxide (e.g. PEO) 46.5 ± 25 46.5 ± 17 46.5 ± 12 46.5 ± 10cellulose ester or ether (e.g. HPMC)  14 ± 7  14 ± 5  14 ± 2.5  14 ± 0.5plasticizer (e.g. PEG) 12.5 ± 10 12.5 ± 7  12.5 ± 5  12.5 ± 3 antioxidant (e.g. α-tocopherol)  0.125 ± 0.12 0.125 ± 0.1   0.125 ± 0.05 0.125 ± 0.03

The pharmaceutical dosage form according to the invention may beproduced by different processes, which are explained in greater detailbelow; the present invention also relates to pharmaceutical dosage formsthat are obtainable by any of the processes described here below:

In general, the process for the production of the pharmaceutical dosageform according to the invention preferably comprises the followingsteps:

-   -   (a) mixing of components (A), (C), optionally (B) and/or (D);    -   (b) optionally pre-forming the mixture obtained from step (a),        preferably by applying heat and/or force to the mixture obtained        from step (a), the quantity of heat supplied preferably not        being sufficient to heat component (C) up to its softening        point;    -   (c) hardening the mixture by applying heat and force, it being        possible to supply the heat during and/or before the application        of force and the quantity of heat supplied being sufficient to        heat component (C) at least up to its softening point;    -   (d) optionally singulating the hardened mixture;    -   (e) optionally shaping the pharmaceutical dosage form; and    -   (f) optionally providing a film coating.

Heat may be supplied directly or with the assistance of ultrasound.Force may be applied and/or the pharmaceutical dosage form may be shapedfor example by direct tabletting or with the assistance of a suitableextruder, particularly by means of a screw extruder equipped with twoscrews (twin-screw-extruder) or by means of a planetary gear extruder.

The shaping of the pharmaceutical dosage form according to the inventionis of particular importance. The final shape of the pharmaceuticaldosage form may either be provided during the hardening of the mixtureby applying heat and force (step (c)) or in a subsequent step (step(e)). In both cases, the mixture of all components is preferably in theplastified state, i.e. preferably, shaping is performed at a temperatureat least above the softening point of component (C).

Shaping can be performed, e.g., by means of a tabletting presscomprising die and plunger of appropriate shape. Preferably, the plungeris a H-plunger so that the cross section of the pharmaceutical dosageform assumes the form of a H.

The following process variants are particularly preferred:

Process Variant 1:

In this embodiment, the pharmaceutical dosage form according to theinvention is preferably produced without using an extruder by preferablymixing components (A), (C), optionally (B) and/or (D) and, optionallyafter granulation, shaping the resultant mixture by application of forceto yield the pharmaceutical dosage form with preceding and/orsimultaneous exposure to heat.

This heating and application of force for the production of thepharmaceutical dosage form proceeds without using an extruder.

Components (A), (C), optionally (B) and/or (D) are mixed in a mixerknown to the person skilled in the art. The mixer may, for example, be aroll mixer, shaking mixer, shear mixer or compulsory mixer.

The resultant mixture is preferably directly shaped into thepharmaceutical dosage form according to the invention by application offorce with preceding and/or simultaneous exposure to heat. The mixturemay, for example, be formed into tablets by direct tabletting. In directtabletting with preceding exposure to heat, the material to be pressedis heated immediately prior to tabletting at least to the softeningtemperature of component (C), preferably to its melting temperature, andthen pressed. In the case of direct tabletting with simultaneousapplication of heat, the mixture to be press-formed is heated at leastto the softening point of polymeric component (C) with the assistance ofthe tabletting tool, i.e. the bottom punch, top punch and the die, andis so press-formed.

This method may also be regarded as a sintering method and the dosageform thus obtained may be regarded as a sintered dosage form. In thisregard, sintering means the solidification of crystalline, granular orpowdered material by growing together of the crystallites when heatedappropriately. The growing together can take place, e.g., by diffusion(solid/solid-reaction). The sintered structure can be analyzed bymethods known in the art, e.g., by (electron)microscopy. As the dosageform contains several components, the sintering method is preferably aso-called “fusion sintering” where one of the components involved melts,wets and coats the higher-melting components. When cooling down, themelted component (re)solidifies. In a preferred embodiment, component(C) is the component that melts while the other components do not meltunder the given conditions. Nonetheless, the other components may—but donot have to—at least partially dissolve in the melted component (C).

By such process using a tabletting tool with bottom punch, top punch anddie, e.g. a powder mixture of all components may be compressed at atemperature of e.g. 80° C., the pressure caused by a force of e.g. 2 kNor 4 kN being maintained for e.g. 15 seconds.

The resultant mixture of components (A), (C), optionally (B) and/or (D)may also first be granulated and then, with preceding and/orsimultaneous exposure to heat, be shaped into the pharmaceutical dosageform according to the invention by application of force.

Granulation may be performed in known granulators by wet granulation ormelt granulation.

Each of the above-mentioned process steps, in particular the heatingsteps and simultaneous or subsequent application of force for productionof the pharmaceutical dosage form according to the invention proceedswithout using an extruder.

Process Variant 2:

In this process variant, the pharmaceutical dosage form according to theinvention is produced by thermoforming with the assistance of anextruder, preferably without there being any observable consequentdiscoloration of the extrudate.

In order to investigate the extent of discoloration due to thisthermoforming, the colour of the mixture of starting components of whichthe pharmaceutical dosage form consists is first determined withoutaddition of a color-imparting component, such as for example a coloringpigment or an intrinsically colored component (for exampleα-tocopherol). This composition is then thermoformed according to theinvention, wherein all process steps, including cooling of theextrudate, are performed under an inert gas atmosphere. By way ofcomparison, the same composition is produced by the same process, butwithout an inert gas atmosphere. The color of the pharmaceutical dosageform produced according to the invention from the starting compositionand of the pharmaceutical dosage form produced by way of comparison isdetermined. The determination is performed with the assistance of“Munsell Book of Color” from Munsell Color Company Baltimore, Md., USA,1966 edition. If the color of the pharmaceutical dosage formthermoformed according to the invention has a color with identificationno. N 9.5, but at most a color with the identification no. 5Y 9/1,thermoforming is classed as being “without discoloration”. If thepharmaceutical dosage form has a color with the identification no. 5Y9/2 or greater, as determined according to the Munsell Book of Color,the thermoforming is classed as being “with discoloration”.

Surprisingly, the pharmaceutical dosage forms according to the inventionexhibit no discoloration classed in accordance with the aboveclassification, if the entire production process is performed under aninert gas atmosphere, preferably under a nitrogen atmosphere with theassistance of an extruder for thermoforming.

This variant according to the invention for the production ofpharmaceutical dosage forms according to the invention is characterizedin that

-   -   z) components (A), (C), optionally (B) and/or (D) are mixed,    -   y) the resultant mixture is heated in the extruder at least up        to the softening point of component (C) and extruded through the        outlet orifice of the extruder by application of force,    -   x) the still plastic extrudate is singulated and formed into the        pharmaceutical dosage form or    -   w) the cooled and optionally reheated singulated extrudate is        formed into the pharmaceutical dosage form,        wherein process steps y) and x) and optionally process steps z)        and w) are performed under an inert gas atmosphere, preferably a        nitrogen atmosphere.

Mixing of the components according to process step z) may also proceedin the extruder.

Components (A), (C), optionally (B) and/or (D) may also be mixed in amixer known to the person skilled in the art. The mixer may, forexample, be a roll mixer, shaking mixer, shear mixer or compulsorymixer.

Before blending with the remaining components, component (C) and/or (D)is preferably provided according to the invention with an antioxidant.This may proceed by mixing the two components, (C) and the antioxidant,preferably by dissolving or suspending the antioxidant in a highlyvolatile solvent and homogeneously mixing this solution or suspensionwith component (C) and the optionally present component (D) and removingthe solvent by drying, preferably under an inert gas atmosphere.

The, preferably molten, mixture which has been heated in the extruder atleast up to the softening point of component (C) is extruded from theextruder through a die with at least one bore.

The process according to the invention requires the use of suitableextruders, preferably screw extruders. Screw extruders which areequipped with two screws (twin-screw-extruders) are particularlypreferred.

The extrusion is preferably performed so that the expansion of thestrand due to extrusion is not more than 50%, i.e. that when using a diewith a bore having a diameter of e.g. 6 mm, the extruded strand shouldhave a diameter of not more than 9 mm. More preferably, the expansion ofthe strand is not more than 40%, still more preferably not more than35%, most preferably not more than 30% and in particular not more than25%. It has been surprisingly found that if the extruded material in theextruder is exposed to a mechanical stress exceeding a certain limit, asignificant expansion of the strand occurs thereby resulting inundesirable irregularities of the properties of the extruded strand,particularly its mechanical properties.

Preferably, extrusion is performed in the absence of water, i.e., nowater is added. However, traces of water (e.g., caused by atmospherichumidity) may be present.

The extruder preferably comprises at least two temperature zones, withheating of the mixture at least up to the softening point of component(C) proceeding in the first zone, which is downstream from a feed zoneand optionally mixing zone. The throughput of the mixture is preferablyfrom 2.0 kg to 8.0 kg/hour.

After heating at least up to the softening point of component (C), themolten mixture is conveyed with the assistance of the screws, furtherhomogenised, compressed or compacted such that, immediately beforeemerging from the extruder die, it exhibits a minimum pressure of 5 bar,preferably of at least 7.5 bar, more preferably at least 10 bar, stillmore preferably at least 12.5 bar, yet more preferably at least 15 bar,most preferably at least 17.5 bar and in particular at least 20 bar, andis extruded through the die as an extruded strand or strands, dependingon the number of bores which the die comprises.

In a preferred embodiment, the die head pressure is within the range offrom 25 to 85 bar. The die head pressure can be adjusted inter alia bydie geometry, temperature profile and extrusion speed.

The die geometry or the geometry of the bores is freely selectable. Thedie or the bores may accordingly exhibit a round, oblong or ovalcross-section, wherein the round cross-section preferably has a diameterof 0.1 mm to 15 mm and the oblong cross-section preferably has a maximumlengthwise extension of 21 mm and a crosswise extension of 10 mm.Preferably, the die or the bores have a round cross-section. The casingof the extruder used according to the invention may be heated or cooled.The corresponding temperature control, i.e. heating or cooling, is soarranged that the mixture to be extruded exhibits at least an averagetemperature (product temperature) corresponding to the softeningtemperature of component (C) and does not rise above a temperature atwhich the pharmacologically active compound (A) to be processed may bedamaged. Preferably, the temperature of the mixture to be extruded isadjusted to below 180° C., preferably below 150° C., but at least to thesoftening temperature of component (C). Typical extrusion temperaturesare 120° C. and 130° C.

In a preferred embodiment, the extruder torque is within the range offrom 25 to 55 N/m. Extruder torque can be adjusted inter alia by diegeometry, temperature profile and extrusion speed.

After extrusion of the molten mixture and optional cooling of theextruded strand or extruded strands, the extrudates are preferablysingulated. This singulation may preferably be performed by cutting upthe extrudates by means of revolving or rotating knives, water jetcutters, wires, blades or with the assistance of laser cutters.

An inert gas atmosphere is not necessary for intermediate or finalstorage of the optionally singulated extrudate or the final shape of thepharmaceutical dosage form according to the invention.

The singulated extrudate may be pelletized with conventional methods orbe press-formed into tablets in order to impart the final shape to thepharmaceutical dosage form. It is, however, also possible not tosingulate the extruded strands and, with the assistance ofcontrarotating calender rolls comprising opposing recesses in theirouter sleeve, to form them into the final shape, preferably a tablet,and to singulate these by conventional methods.

Should the optionally singulated extrudate not immediately be formedinto the final shape, but instead cooled for storage, after the periodof storage an inert gas atmosphere, preferably a nitrogen atmosphere,should be provided and must be maintained during heating of the storedextrudate up until plasticization and definitive shaping to yield thepharmaceutical dosage form.

The application of force in the extruder onto the at least plasticizedmixture is adjusted by controlling the rotational speed of the conveyingdevice in the extruder and the geometry thereof and by dimensioning theoutlet orifice in such a manner that the pressure necessary forextruding the plasticized mixture is built up in the extruder,preferably immediately prior to extrusion. The extrusion parameterswhich, for each particular composition, are necessary to give rise to apharmaceutical dosage form with a resistance to crushing of at least 400N, preferably of at least 500 N, may be established by simplepreliminary testing.

For example, extrusion may be performed by means of atwin-screw-extruder type Micro 27 GL 40 D (Leistritz, Nurnberg,Germany), screw diameter 27 mm. Screws having eccentric ends may beused. A heatable die with a round bore having a diameter of 8 mm may beused. The entire extrusion process should be performed under nitrogenatmosphere. The extrusion parameters may be adjusted e.g. to thefollowing values: rotational speed of the screws: 100 Upm; deliveryrate: 4 kg/h; product temperature: 125° C.; and jacket temperature: 120°C.

Process Variant 3:

In this process variant for the production of the pharmaceutical dosageform according to the invention energy is applied to a mixture of thecomponents by means of ultrasonication.

First of all a homogeneous mixture of at least component (A) andcomponent (C) (=binder) is produced. Further auxiliary substances, suchas for example fillers, plasticisers, slip agents or dyes, may also beincorporated into this mixture. A low molecular weight polyethyleneglycol is preferably used as plasticizers.

Mixing may be performed with the assistance of conventional mixers.Examples of suitable mixers are roll mixers, which are also known astumbler, drum or rotary mixers, container mixers, barrel mixers (drumhoop mixers or tumbling mixers) or shaking mixers, shear mixers,compulsory mixers, plough bar mixers, planetary kneader-mixers, Zkneaders, sigma kneaders, fluid mixers or high-intensity mixers.

Selection of the suitable mixer is determined inter alia by theflowability and cohesiveness of the material to be mixed.

The mixture is then subjected to shaping. The mixture is preferablyshaped during or after ultrasonication, preferably by compaction.

It is particularly preferred during ultrasonication that there is directcontact between the mixture and the sonotrode of the ultrasound device.

A frequency of 1 kHz to 2 MHz, preferably of 15 to 40 kHz, should bemaintained during ultrasonication. Ultrasonication should be performeduntil softening of the polymer (C) is achieved. This is preferablyachieved within a few seconds, particularly preferably within 0.1 to 5seconds, preferably 0.5 to 3 seconds.

Ultrasonication and the application of force ensure uniform energytransfer, so bringing about rapid and homogeneous sintering of themixture. In this manner, pharmaceutical dosage forms are obtained whichhave a resistance to crushing of at least 400 N, preferably of at least500 N, and thus cannot be pulverized.

Before shaping is performed, the mixture may be granulated after themixing operation, after which the resultant granules are shaped into thepharmaceutical dosage form with ultrasonication and application offorce.

Granulation may be performed in machinery and apparatus known to theperson skilled in the art.

If granulation is performed as wet granulation, water or aqueoussolutions, such as for example ethanol/water or isopropanol/water, maybe used as the granulation liquid.

The mixture or the granules produced therefrom may also be subjected tomelt extrusion for further shaping, wherein the mixture is convertedinto a melt by ultrasonication and exposure to force and then extrudedthrough a dies. The strands or strand obtained in this manner may besingulated to the desired length using known apparatus. The formedarticles singulated in this manner may optionally furthermore beconverted into the final shape with ultrasonication and application offorce.

Final shaping to yield the pharmaceutical dosage form preferablyproceeds with application of force in appropriate moulds.

The above-described formed articles may also be produced with acalendering process by initially plasticising the mixture or thegranules produced therefrom by means of ultrasonication and applicationof force and performing extrusion through an appropriate die. Theseextrudates are then shaped into the final shape between twocontrarotating shaping rolls, preferably with application of force.

As already mentioned, shaping to yield the final shape of thepharmaceutical dosage form by using a mixture comprisingpharmacologically active compound (A) and polymer (C) proceedspreferably in powder form by direct compression with application offorce, wherein ultrasonication of this mixture is provided before orduring the application of force. The force is at most the force which isconventionally used for shaping pharmaceutical dosage forms, such astablets, or for press-forming granules into the corresponding finalshape.

The tablets produced according to the invention may also be multilayertablets.

In multilayer tablets, at least the layer which containspharmacologically active compound (A) should be ultrasonicated andexposed to force.

The corresponding necessary application of force may also be applied tothe mixture with the assistance of extruder rolls or calender rolls.Shaping of the pharmaceutical dosage forms preferably proceeds by directpress-forming of a pulverulent mixture of the components of thepharmaceutical dosage form or corresponding granules formed therefrom,wherein ultrasonication preferably proceeds during or before shaping.Such exposure continues until the polymer (C) has softened, which isconventionally achieved in less than 1 second to at most 5 seconds.

A suitable press is e.g. a Branson WPS, 94-003-A, pneumatical (BransonUltraschall, Dietzenbach, Germany) having a plain press surface. Asuitable generator (2000 W) is e.g. a Branson PG-220A, 94-001-A analogue(Branson Ultraschall) with a sonotrode having a diameter of 12 mm. A diehaving a diameter of 12 mm may be used, the bottom of the die beingformed by a bottom punch having a plain press-surface and a diameter of12 mm. Suitable parameters for plastification are frequency: 20 kHz;amplitude: 50%; force: 250 N. The effect of ultrasound and force bymeans of the sonotrode may be maintained for e.g. 0.5 seconds, andpreferably both effects take place simultaneously.

Process Variant 4:

In this process variant for the production of the pharmaceutical dosageform according to the invention, components (A), (C), optionally (B),such as antioxidants, plasticizers and/or delayed-release auxiliarysubstances, and optionally component (D), are processed with theassistance of a planetary-gear extruder to yield the pharmaceuticaldosage form according to the invention.

Planetary-gear extruders are known and described inter alia in detail inHandbuch der Kunststoff-Extrusionstechnik I (1989) “Grundlagen” inChapter 1.2 “Klassifizierung von Extrudern”, pages 4 to 6. Thecorresponding description is hereby introduced as a reference and isdeemed to be part of the disclosure.

The mixture is conveyed into the feed zone of the planetary-gearextruder. By heating at least to the softening point of component (C),the mixture is melted and the molten mixture is conveyed into the areaof the central spindle, i.e. the extrusion zone, by the interaction ofthe central spindle 3 and the planetary spindles 4, further homogenized,compressed or compacted and extruded through the die 8 as an extrudedstrand or extruded strands, depending on how many bores the diecomprises. The die geometry or the geometry of the bores is freelyselectable. Thus, the die or the bores may exhibit a round, oblong oroval cross-section, wherein the round cross-section preferably has adiameter of 0.1 mm to 15 mm and the oblong cross-section preferably hasa maximum lengthwise extension of 21 mm and a crosswise extension of 10mm. The extrusion die may also take the form of a slot die. Preferably,the die or the bores have a round, oval or oblong cross-section. Boththe casing 6 of the planetary-gear extruder used according to theinvention and the central spindle may be heated or cooled. Thecorresponding temperature control, i.e. heating or cooling, is soarranged that the mixture to be extruded exhibits an average temperaturecorresponding to the softening temperature of component (C) and does notrise above a temperature at which component (A) to be processed may bedamaged. Preferably, the temperature of the mixture to be extruded isadjusted to below 180° C., preferably below 150° C., but at least to thesoftening temperature of component (C).

After extrusion of the molten mixture and optional cooling of theextruded strand or extruded strands, the extrudates are singulated. Thissingulation may preferably be performed by cutting up the extrudates bymeans of revolving or rotating knives, water jet cutters, wires, bladesor with the assistance of laser cutters.

Optionally after further cooling of the singulated extrudates, which arepreferably present in the form of disks, they are optionally re-shapedinto the final shape of the pharmaceutical dosage form, wherein they maybe exposed to heat again if necessary.

This shaping for example into tablets may proceed in that the plasticextrudate is shaped with press-forming with the assistance of twocontrarotating rolls preferably with mutually opposing recesses forplastification in the roll sleeve, the construction of which recessesdetermines the tablet shape.

However, it is also possible to form the tablets from the singulatedextrudates in each case with the assistance of an optionally heated dieand at least one shaping punch. To this end, the cylindrical granulesobtained after singulation of the extruded strand may preferably beused. Apart from being press-formed into tablets, these granules orother multiparticulate shapes obtained, such as pellets or spheroids,may also be packaged into capsules in order to be used as apharmaceutical dosage form produced according to the invention.

In a further preferred embodiment, the extruded strands extruded througha plurality of bores in the extrusion die may, after cooling thereof,optionally be brought together by interlacing or wrapping in the mannerof rope production to yield a thicker strand than the individualextruded strands. This strand may optionally be further processed bysolvent attack with a suitable solvent or by heating to the softeningpoint of the polymer (C) and optionally removing the solvent inaccordance with the above-stated singulation and shaping of anindividual strand.

If necessary, the planetary-gear extruder used may comprise not only anextrusion zone but also at least one further zone, so that the mixtureto be extruded may optionally also be degassed.

The process according to the invention may be performed discontinuouslyor continuously, preferably continuously.

A suitable extruder, for example, is a planetary gear extruder type BCG10 (LBB Bohle, Ennigerloh, Germany) having four planetary spindles andan extrusion die with bores having a diameter of 8 mm. A gravimetricaldosing of 3.0 kg/h is suitable. The extrusion may be performed, forexample, at a rotational speed of 28.6 rmp and a product temperature ofabout 88° C.

Process Variant 5:

This variant for the production of the pharmaceutical dosage formaccording to the invention is performed by processing at least thecomponents (A), (C), optionally (B), such as antioxidants, plasticizersand/or delayed-release auxiliary substances, and optionally component(D), with addition of a solvent for component (C), i.e. for the polymeror polymers (C), to yield the pharmaceutical dosage form.

To this end, components (A), (C), optionally (B) and/or (D) are mixedand, after addition of the solvent and optionally after granulation, theresultant formulation mixture is shaped to yield the pharmaceuticaldosage form.

Components (A), (C), optionally (B) and/or (D) are mixed in a mixerknown to the person skilled in the art. The mixer may, for example, be aroll mixer, shaking mixer, shear mixer or compulsory mixer.

The solvent for the polymer (C) is added at least in such quantitiesthat the formulation mixture is uniformly moistened.

Solvents which are suitable for the polymer (C) are preferably aqueoussolvents, such as water, mixtures of water and aliphatic alcohols,preferably C₁ to C₆ alcohols, esters, ethers, hydrocarbons, particularlypreferably distilled water, short-chain alcohols, such as methanol,ethanol, isopropanol, butanol or aqueous alcohol solutions.

The solvent is preferably added with stirring. The uniformly moistenedcomposition is then dried. Drying preferably proceeds with exposure toheat at temperatures at which it is possible to rule out anydiscoloration of the composition. This temperature may be established bysimple preliminary testing.

Before or after drying, the composition may be divided into sub-portionswhich preferably in each case correspond to the mass of a unit of thepharmaceutical dosage form. The corresponding dried portions are thenshaped to yield the pharmaceutical dosage form.

This is preferably achieved by using tablet presses.

The formulation mixture may also be moistened in such a manner that,before addition of the solvent, the formulation mixture is divided,preferably in moulds, into sub-portions, is dispersed in a liquiddispersant with stirring and then the solvent is added. Component (C) isnot soluble in the dispersant, which must be miscible with the solvent.

Suitable dispersants are preferably hydrophilic solvents, such asaliphatic alcohols, ketones, esters. Short-chain alcohols are preferablyused.

Alternatively, the formulation mixture may also be moistened in such amanner that the solvent is incorporated into the formulation mixture asa foam. Such a foam of the solvent is preferably produced with theassistance of a high-speed mixer, preferably with the addition ofconventional foam stabilizers. Suitable stabilizers are, for example,hydrophilic polymers such as for example hydroxypropylmethylcellulose.

The foam is also preferably incorporated into the formulation mixturewith stirring, a granulated composition so preferably being obtained.

Before or after being divided into sub-portions, which preferablycorrespond to the mass of a unit of the pharmaceutical dosage form, thegranulated composition is dried and then shaped into the pharmaceuticaldosage form.

Drying and shaping may preferably proceed as described above. Theprocess according to the invention may also be performed in such amanner that solvent is added to the formulation mixture in such aquantity that a shapeable paste is obtained.

Before or after being dried, which may proceed as explained above, sucha paste may be divided into sub-portions and the dried portions, afterfurther division in each case into a portion corresponding to the massof a unit of the pharmaceutical dosage form, are shaped or converted toyield the pharmaceutical dosage form.

It is here possible to form the sub-portions in the form of strands,which may be produced with the assistance of a screen or a strandformer. The dried strands are preferably singulated and shaped to yieldthe pharmaceutical dosage form. This shaping preferably proceeds withthe assistance of a tablet press, using shaping rollers or shaping beltsequipped with rollers.

It is also possible to convert the paste into a planar structure and tostamp the pharmaceutical dosage form out of it once it has dried.

The paste is advantageously processed with an extruder, wherein,depending on the configuration of the extrusion, strands or planarstructures articles are produced, which are singulated by chopping,cutting or stamping. The singulated sub-portions may be shaped, formedor stamped as described above to yield the pharmaceutical dosage form.Corresponding apparatuses are known to the person skilled in the art.

The process according to the invention may here be performedcontinuously or discontinuously.

It is also possible to add solvent to the formulation mixture in such aquantity that at least the polymer component (C) is dissolved. Such asolution or dispersion/suspension is preferably converted into a planarstructure, an extruder with a flat die preferably being used or thesolution being cast onto a planar support.

As stated above, after drying, the pharmaceutical dosage forms may beobtained from the planar structures by stamping or calendering. It isalso possible, as stated above, to convert the solution into strands andto singulate these, preferably after they have been dried, and shapethem to yield the pharmaceutical dosage form.

Alternatively, the solution may also be divided into portions such that,after drying, they each correspond to the mass of a unit of thepharmaceutical dosage form, with moulds which already correspond to theshape of the unit of the pharmaceutical dosage form preferably beingused for this purpose.

If the solution is divided into any desired portions, the portions may,after drying, optionally be combined again and be shaped to form thepharmaceutical dosage form, being for example packaged in a capsule orpress-formed to form a tablet.

The formulation mixtures combined with solvent are preferably processedat temperatures of 20° C. to 40° C., wherein, apart from during dryingto remove the solvent and the optionally present dispersant, no highertemperatures are used. The drying temperature must be selected below thedecomposition temperature of the components. After shaping to yield thepharmaceutical dosage form, further drying corresponding to theabove-described drying may optionally be performed.

Combinations of individual process steps of the above process variantsare also possible in order to produce the pharmaceutical dosage formaccording to the invention.

Process variants 2 and 4 as described above involve the extrusion of acomposition comprising components (A), (C), optionally (B) and/or (D).Preferably, extrusion is performed by means of twin-screw-extruders orplanetary-gear-extruders, twin-screw extruders being particularlypreferred.

The process for the preparation of the pharmaceutical dosage formaccording to the invention is preferably performed continuously.Preferably, the process involves the extrusion of a homogeneous mixtureof components (A), (C), optionally (B) and/or (D). It is particularlyadvantageous if the obtained intermediate, e.g. the strand obtained byextrusion, exhibits uniform properties. Particularly desirable areuniform density, uniform distribution of the active compound, uniformmechanical properties, uniform porosity, uniform appearance of thesurface, etc. Only under these circumstances the uniformity of thepharmacological properties, such as the stability of the releaseprofile, may be ensured and the amount of rejects can be kept low.

Preferably, the process according to the present invention may beperformed with less than 25% rejects, more preferably less than 20%,most preferably less than 15% and in particular less than 10% rejects,wherein the criteria for rejection are the FDA standards regarding theintervariability of the content of component (A), its release profileand/or the density of the pharmaceutical dosage form when comparing twopharmaceutical dosage forms, preferably taken from the same batch.

It has been surprisingly found that the above properties may be obtainedby means of twin-screw-extruders and planetary-gear-extruders,twin-screw-extruders being particularly preferred.

Further, it has been surprisingly found that extrudates exhibiting anadvantageous morphology are obtainable by means ofplanetary-gear-extruders and twin-screw-extruders. It has been foundthat under suitable conditions the extrudate is surrounded by a shellwhich may be denoted as “extrusion skin”. Said extrusion skin can beregarded as a collar-like or tubular structure forming a circumferentialsection of the extrudate about its longitudinal extrusion axis so thatthe outer surface of said collar-like or tubular structure forms theclosed shell of the extrudate. Usually, only the front faces of theextrudate are not covered by said extrusion skin.

The extrusion skin surrounds the core of the extrudate in a collar-likeor tubular arrangement and preferably is connected therewith in aseamless manner. The extrusion skin differs from said core in itsmorphology. Usually, the extrusion skin is visible with the naked eye inthe cross-section of the extrudate, optionally by means of a microscope,since due to the different morphology of the material forming theextrusion skin and the material forming the core, the optical propertiesdiffer as well. It seems that during extrusion the material forming theextrusion skin is exposed to mechanical and thermal conditions differingfrom the conditions the core of the extrudate is exposed to. Inconsequence, a heterogeneous morphology of the extruded strand isobtained, which e.g. assumes radial symmetry when an extrusion diehaving circular shape is used. The material forming the extrusion skinand the material forming the core are usually distinguished by theirmorphology, preferably, however, not by their composition, particularlynot by the relative content of components (A), (C), optionally (B)and/or (D).

Usually the extrusion skin covers the entire shell of the extrudate likea one-piece collar, independently of what geometry has been chosen forthe extrusion die. Therefore, the extrudate may assume circular,elliptic or other cross-sections.

The extrusion skin is preferably characterized by a unitary thickness.Preferably, the thickness of the extrusion skin is within the range from0.1 to 4.0 mm, more preferably 0.15 to 3.5 mm, still more preferably 0.2to 3.0 mm, most preferably 0.2 to 2.5 mm and in particular 0.2 to 2.0mm. In a preferred embodiment the thickness of the extrusion skin in thesum over both opposing sides amounts to 0.5 to 50%, more preferably 1.0to 40%, still more preferably 1.5 to 35%, most preferably 2.0 to 30% andin particular 2.5 to 25% of the diameter of the extrudate.

When the pharmaceutical dosage forms according to the invention areprepared by means of extrusion processes which lead to intermediateshaving an extrusion skin as described above, the pharmaceutical dosageforms obtained therefrom are preferably also characterized by aparticular morphology.

In a preferred embodiment those regions, which have formed the extrusionskin in the extruded intermediate, are still visible with the naked eye,optionally by means of a microscope, in the cross-section of thepharmaceutical dosage form. This is because usually by furtherprocessing the extrudate, particularly by singulating and/or shaping,the different nature and thereby also the different optical propertiesof the material forming the extrusion skin and the material forming thecore are maintained. In the following, that domain of the pharmaceuticaldosage forms which has emerged from the extrusion skin in the course offurther processing the extruded intermediate, will be denoted as “skindomain”.

Preferably, the pharmaceutical dosage form according to the inventioncomprises a skin domain and a core located therein. Preferably, the skindomain is connected with the core in a seamless manner. Preferably theskin domain as well as the core have substantially the same chemicalcomposition, i.e. substantially the same relative content of components(A), (C), optionally (B) and/or (D). The material forming the skindomain has a morphology differing from the material forming the core.Usually, this different morphology is also expressed in terms ofdifferent optical properties, so that the skin domain and the core arevisible with the naked eye in the cross-section of the pharmaceuticaldosage form.

In case that the pharmaceutical dosage form has been coated, e.g. by afilm coating, the skin domain is located between the film coating andthe core.

Since the pharmaceutical dosage form according to the invention may beobtained in different ways from the extrudate containing the extrusionskin (intermediate), the skin domain may take different arrangements andextensions within the pharmaceutical dosage form according to theinvention. All arrangements have in common, however, that the skindomain partially covers the surface of the core, but usually not itsentire surface. Preferably, two opposing surfaces of the core are not,or at least not fully covered by the skin domain. In other words,preferably the skin domain has two openings/blanks on opposing sides.

The thickness of the skin domain may be uniform. It is also possible,however, that in the course of the processing, i.e. due to thesubsequent shaping (e.g. press-forming) of the extrudate, varioussections of the extrusion skin are expanded or compressed differentlythereby leading to a variation of the thickness of the skin domainwithin the pharmaceutical dosage form.

Preferably the thickness of the skin domain is within the range from 0.1to 4.0 mm, more preferably 0.15 to 3.5 mm, still more preferably 0.2 to3.0 mm, most preferably 0.2 to 2.5 mm and in particular 0.2 to 2.0 mm.

The process according to the invention preferably involves the extrusionof a mixture of components (A), (C), optionally (B) and/or (D),preferably by means of a planetary-gear-extruder or atwin-screw-extruder. After extrusion the extrudate is preferablysingulated, shaped and optionally coated in order to obtain the finalpharmaceutical dosage form.

In a preferred embodiment of the process according to the invention,shaping is performed in the plasticized state of the mixture ofcomponents (A), (C), optionally (B) and/or (D). It has been surprisinglyfound that the extrusion of certain polymers (C), particular of highmolecular weight polyethylene oxides, yields intermediates exhibitingsome kind of memory effect: when the singulated extrudates are shaped atambient temperature, e.g. by press-forming, pharmaceutical dosage formsare obtained which tend to regain their original outer form upon storageunder stressed storage conditions, i.e. they return to the form they hadprior to shaping.

The shape of the pharmaceutical dosage form upon storage at stressedconditions, e.g. at 40° C./75% RH, may also be unstable for otherreasons.

Said memory effect significantly deteriorates the storage stability ofthe pharmaceutical dosage form, as by regaining its outer form severalproperties of the pharmaceutical dosage form are changed. The sameapplies to any changes of the outer form due to other reasons.

It has been found that, for example, depending on the extrusionconditions a significant expansion of the strand may occur therebyresulting in an increase of the volume of the extrudate, i.e. a decreaseof its density. Said expansion may be compensated by subsequentlypress-forming the singulated extrudate at a sufficient pressure, sinceunder these conditions the expansion of the material may be reversed.

However, if press-forming has been performed at ambient temperature, thememory effect of the compressed extrudate will cause it to swell and toexpand upon storage, thereby significantly increasing the volume of thepharmaceutical dosage form.

It has been surprisingly found that such memory effect may be suppressedif shaping of the singulated extrudate is performed at increasedtemperature, i.e. in the plasticized state of the mixture of components(A), (C), optionally (B) and/or (D). Preferably, shaping is performed ata pressure of at least 1 kN, more preferably within the range from 2 kNto 50 kN, e.g. by means of a tablet press. Preferably, shaping isperformed at a temperature which preferably is about 40° C., morepreferably about 30° C. and in particular about 25° C. below the meltingrange of the mixture of components (A), (C), optionally (B) and/or (D).The melting range of a given mixture may be determined by conventionalmethods, preferably by DSC (e.g. with a DSC model 2920 (TA Instruments,New Castle) and ultrahigh pure nitrogen as purge gas at a flow rate of150 ml/min; approximate sample weight of 10-20 mg, sealed in nonhermeticaluminium pans; temperature ramp speed 10° C./min).

In a preferred embodiment the outer shape of the pharmaceutical dosageform according to the invention does not substantially change when beingstored for at least 12 h, preferably for at least 24 h, at 40° C. and75% RH, preferably in an open container.

In a preferred embodiment the volume of the pharmaceutical dosage formaccording to the invention increases by not more than 20% or 17.5%, morepreferably not more than 15% or 12.5%, still more preferably not morethan 10% or 7.5%, most preferably not more than 6.0%, 5.0% or 4.0% andin particular not more than 3.0%, 2.0% or 1.0% when being stored for atleast 12 h, preferably for at least 24 h, at a temperature of 20° C.below the melting range of the mixture of components (A), (C),optionally (B) and/or (D), optionally at a temperature of 40° C. and 75%RH.

A further aspect of the invention relates to a packaging containing thepharmaceutical dosage form according to the invention and an oxygenscavenger. Suitable packages include blister packages and bottles, suchas glass bottles or bottles made from thermoplastic polymers.

Oxygen scavengers and the application thereof in pharmaceuticalpackaging are known to the skilled artisan. In a preferred embodiment,the oxygen scavenger is selected from the group consisting ofmetal-catalyzed oxidizable organic polymers and anti-oxidants. It hasbeen surprisingly found that the storage stability of the pharmaceuticaldosage form can be increased when keeping the oxygen content of theatmosphere within the packaging low. Methods for packagingpharmaceutical dosage forms and the application of suitable oxygenscavengers are known to the skilled artisan. In this regard it can bereferred to e.g. D. A. Dean, Pharmaceutical Packaging Technology, Taylor& Francis, 1st ed.; F. A. Paine et al., Packaging Pharmaceutical andHealthcare Products, Springer, 1st ed.; and O. G. Piringer et al.,Plastic Packaging: Interactions with Food and Pharmaceuticals,Wiley-VCH, 2nd ed.

The pharmaceutical dosage form according to the invention is suitable toavoid various misuses, particularly

-   -   accidental misuse (e.g. unintentional);    -   recreational misuse; and    -   experienced drug misuse.

A further aspect of the invention relates to the use of an opioid forthe manufacture of the pharmaceutical dosage form as described above forthe treatment of pain.

A further aspect of the invention relates to the use of a pharmaceuticaldosage form as described above for avoiding or hindering the abuse ofthe pharmacologically active compound (A) contained therein.

A further aspect of the invention relates to the use of a pharmaceuticaldosage form as described above for avoiding or hindering theunintentional overdose of the pharmacologically active compound (A)contained therein.

In this regard, the invention also relates to the use of apharmacologically active compound (A) as described above and/or asynthetic or natural polymer (C) as described above for the manufactureof the pharmaceutical dosage form according to the invention for theprophylaxis and/or the treatment of a disorder, thereby preventing anoverdose of the pharmacologically active compound (A), particularly dueto comminution of the pharmaceutical dosage form by mechanical action.

Further, the invention relates to a method for the prophylaxis and/orthe treatment of a disorder comprising the administration of thepharmaceutical dosage form according to the invention, therebypreventing an overdose of the pharmacologically active compound (A),particularly due to comminution of the pharmaceutical dosage form bymechanical action. Preferably, the mechanical action is selected fromthe group consisting of chewing, grinding in a mortar, pounding, andusing apparatuses for pulverizing conventional pharmaceutical dosageforms.

The invention is explained below with reference to examples. Theseexplanations are given merely by way of example and do not limit thegeneral concept and scope of the invention.

Example 1 Formulation Examples A. Formulation Examples for RetardedRelease Formulations

Active ingredient(s) 0.01-50% (w/w) Viscous hydrophilic polymer(s)0.01-80% (w/w) Pregelatinized starch 5-80% (w/w) Pharmaceuticallyacceptable formulating agents ad 100% (w/w). Active ingredient(s)0.01-50% (w/w) Viscous hydrophilic polymer(s) comprising 0.01-80% (w/w)hydroxypropyl cellulose Pregelatinized starch 5-80% (w/w)Pharmaceutically acceptable formulating agents ad 100% (w/w). Activeingredient(s) 0.01-50% (w/w) Viscous hydrophilic polymer(s) 0.01-80%(w/w) Pregelatinized starch 5-15% (w/w) Pharmaceutically acceptableformulating agents ad 100% (w/w). Active ingredient(s) 0.01-50% (w/w)Viscous hydrophilic polymer(s) comprising 0.01-80% (w/w) hydroxypropylcellulose Pregelatinized starch 5-15% (w/w) Pharmaceutically acceptableformulating agents ad 100% (w/w). Active ingredient(s) 0.01-50% (w/w)Viscous hydrophilic polymer(s) 0.01-80% (w/w) Pregelatinized starch 5%(w/w) Pharmaceutically acceptable formulating agents ad 100% (w/w).Active ingredient(s) 0.01-50% (w/w) Viscous hydrophilic polymer(s)comprising 0.01-80% (w/w) hydroxypropyl cellulose Pregelatinized starch5% (w/w) Pharmaceutically acceptable formulating agents ad 100% (w/w).Active ingredient(s) 0.01-50% (w/w) Hydroxypropyl cellulose 25-62% (w/w)Hydroxypropyl methylcellulose 0-16% (w/w) Pregelatinized starch 5-15%(w/w) Pharmaceutically acceptable formulating agents ad 100% (w/w).

The above formulations can generally be prepared according to thefollowing process:

-   (1.a) one or more active ingredients, pregelatinized starch, one or    more viscous hydrophilic polymers and optionally some or all of the    pharmaceutically acceptable formulating agents are mixed;-   (1.b) the powder mixture prepared under (1.a) is run through a    compactor, thus yielding plates;-   (1.c) the resulting plates are broken down and sieved, thus yielding    granules;-   (1.d) the resulting granules are optionally mixed with all or the    remainder of the pharmaceutically acceptable formulating agents,    preferably until homogeneous.

In case the active ingredient(s) is a sparingly water soluble, slightlywater soluble, very slightly water soluble, practically water insolubleor water insoluble drug or a drug with a pH dependent solubility, inparticular an alkaline drug, the active ingredient(s) can in oneembodiment be incorporated in the controlled release formulation as anintimate mixture with a cyclodextrin or derivatives thereof or anotherwater soluble polymer, as described hereinabove. In said case, thepreparation of the present controlled release formulation comprises anadditional first step, namely

-   (2.a) one or more active ingredients and the water soluble polymer    are intimately mixed;-   (2.b) the intimate mixture prepared under (2.a) is mixed with    pregelatinized starch, one or more viscous hydrophilic polymers and    optionally some or all of the pharmaceutically acceptable    formulating agents;-   (2.c) the powder mixture prepared under (2.b) is run through a    compactor, thus yielding plates;-   (2.d) the resulting plates are broken down and sieved, thus yielding    granules;-   (2.e) the resulting granules are optionally mixed with all or the    remainder of the pharmaceutically acceptable formulating agents,    preferably until homogeneous.

The formulation obtained by the processes as described hereinabove inone embodiment can then be compressed in a tablet according to theinvention by tabletting in a tabletting machine with punches and diesadapted for the tablet of the invention the final blend resulting fromthe above described processes, i.e. the blend resulting under (1.d) or(2.e).

A compactor as mentioned in step (1.b) or (2.c) of the above describedprocesses is an apparatus wherein the powdery mixture is run between tworollers exerting pressure on the powdery mixture. In this way themixture is compacted and sheets or plates are formed. Compactors arecommercially available, for instance, from the company Gerteis (Jona,Swiss), e.g. a Polygran 3W compactor.

The above general route of preparation of the controlled releaseformulation may be modified by a person skilled in the art by forinstance adding certain ingredients at other stages than indicatedabove.

As an alternative to the above described route of preparation involvinga compaction step, the above described mixture can also be tablettedusing direct compression. When using the technique of directcompression, dies or matrices in the form of the desired tablets of theinvention are filled with a powdery mixture having the tabletcomposition and then are punched with punches adapted for the desiredtablet. The advantage of this way of tabletting is that it usuallyrequires less steps. Apparatuses for direct compression tabletting areknown to the skilled parson. These apparatuses require forced feedingsystems whenever the rheological properties of the mixture are notappropriate to fill the dies or matrices without forced feeding.

Example of a Retarded Release Formulation According to the Invention

Cisapride-(L)-tartrate 52.92 mg Lactose monohydrate 200 mesh 149.43 mgHydroxypropyl methylcellulose 2208 74.1 mg Hydroxypropyl cellulose228.00 mg Drum dried waxy maize starch 28.5 mg Magnesium stearate 2.85mg Colloidal anhydrous silica 5.7 mg Talc 28.5 mg

Preparation of the Above Powder Mixture

Cisapride-(L)-tartrate, hydroxypropyl methylcellulose, hydroxypropylcellulose, drum dried waxy maize starch, the lactose filler, are mixedin a planetary mixer, and than compacted using a dry compactor. Thecompact is broken down, sieved and mixed in a planetary mixer withcolloidal anhydrous silica. Magnesium stearate is added and mixed.

The above mixture can then be compressed into a tablet according to theinvention.

B. Formulation Examples for Immediate Release Formulations

A mixture of 100 g of active ingredient(s), 570 g lactose and 200 gstarch is mixed well and thereafter humidified with a solution of 5 gsodium dodecyl sulfate and 10 g polyvinylpyrrolidone (Kollidon-K 90®) inabout 200 ml of water. The wet powder mixture is sieved, dried andsieved again. Then there are added 100 g microcrystalline cellulose(Avicel®) and 15 g hydrogenated vegetable oil (Sterotex®). The whole ismixed well.

The above mixture can then be compressed into tablets according to theinvention, giving 10.000 tablets, each comprising 10 mg of the activeingredient.

Example 2

Pharmaceutical dosage forms were manufactured from the followingcompositions:

I-1 (#1) I-2 (#2) C-1 tapentadol HCl 291.20 291.20 291.20 PEO Mw 7 Miog/mol 245.00 245.00 PEO Mw 5 Mio g/mol 247.70 polyethylene glycole 600065.10 65.10 65.00 HPMC 100,000 mPas 98.00 98.00 45.50 α-tocopherole 0.700.70 0.65 SUM 700.00 700.00 650.00 tablet format 9 × 21 H0 9 × 21 H0 9 ×21 oblong 291.20 mg tapentadol HCl correspond to 250 mg tapentadol freebase.

General Procedure:

The polyethylene oxide was melted at 90° C. and the total amount ofα-tocopherol was dissolved therein. Then, tapentadol and hydroxypropylmethyl cellulose (HPMC) were mixed in a fast mixer for 5 min at atemperature of 70° C. The melt of polyethylene oxide and α-tocopherolewas added to the mixture dropwise within 10 minutes. The thus obtainedgranulate was sieved on a taper sieving machine and then mixed in a freefall mixer for 15 min. The powder mixture was dosed gravimetrically toan extruder. Extrusion was performed by means of a twin screw extruderof type Micro 27 GL 40 D (Leistritz, Nurnberg, Germany) that wasequipped with a heatable round die having a diameter of 8 mm.

The following extrusion conditions were adjusted:

Number of revolutions of screws: 100 Upm Throughput: 4 kg/h Producttemperature: 120° C. Shell temperature: 100° C.

The hot extrudate was cooled on a conveyor belt and the cooled extrusionstrand was comminuted to cut pieces weighing 700 mg each. The cut pieceswere shaped by means of an excenter press. The tablets of inventiveexamples 1-1 and 1-2 were shaped by means of an H-plunger (9*21 H0, type21×9 WR 1.9 with “inner courtyard”, Notter, Ölbronn-Dürrn, Germany) andthe tablets of comparative example C-1 were shaped by means of aconventional oblong plunger.

The tablets of inventive examples 1-1 and 1-2 had the followingdimensions (base height H according to FIG. 9B); width, height andlength a, b and c according to FIG. 10) (average values n=10):

a 9.06 The manufacturer of the H0-plunger provides a₁ 3.17 the followingformula for the surface and the a₂ 2.72 volume of the shaped tablets asa function a₃ 3.17 of the base height (H): b 4.52 volume = 94.3 + 171.6× H [mm³] = 638.3 mm³ b₁ 0.99 surface = 382 + 52.3 × H [mm²] = 547.8 mm²b₂ 2.54 b₃ 0.99 c 20.49 c₁ 3.26 c₂ 13.97 c₃ 3.26 H 3.17

In comparison, the surface of the pharmaceutical dosage form accordingto comparative example C-1 was estimated to be about 459 mm² (estimationin accordance with Eudragit® Application Guidelines, 10th edition,July/2007, Röhm GmbH, Darmstadt, page 25).

The correlation of the pharmaceutical dosage forms according toinventive examples I-1 and I-2 and according to comparative example C-1with the requirement S≧A·W^(2/3) are summarized in the following table:

I-1/I-2 C-1 weight W 700 mg 650 mg surface S 548 mm² 459 mm² S/W 0.7830.706 A [for S = A · W^(2/3)] 6.95  6.12 

Example 3

The dissolution profile of the tablets was investigated under thefollowing conditions: Paddle apparatus equipped with sinker, 50 rpm,37±5° C., 900 mL simulated intestinal fluid pH 6.8 (phosphate buffer).

The results are displayed in FIGS. 21 to 24.

FIG. 21 shows that immediately after manufacture the release profile ofthe tablet according to inventive example I-2 (H-shape) is comparable tothe release profile of the tablet according to comparative example C-1(oblong).

FIG. 22 shows that the release profile of the tablet according toinventive example I-1 (H-shape) is comparable to the release profile ofthe tablet according to inventive example I-2 (H-shape), i.e. thatdifferent batches provide reproducible results.

FIG. 23 shows that the release profile of the tablet according tocomparative example C-1 (oblong) changes upon storage (40° C., 6 months;25° C. 9 months; and 30° C. 9 months, respectively).

FIG. 24 shows that the release profile of the tablet according toinventive example I-2 (H-shape) is stable, i.e. does not change uponstorage (40° C., 6 months; 25° C. 9 months; and 30° C. 9 months,respectively).

These experimental findings demonstrate that the pharmaceutical dosageforms according to the invention have a storage stability in terms ofthe release profile that is better than the storage stability ofcomparative pharmaceutical dosage forms.

Example 4

In accordance with example 2, pharmaceutical dosage forms weremanufactured from the following compositions:

[mg] C-2 C-3 C-4 I-3 I-4 tapentadol HCl 58.24 116.48 174.72 232.96291.20 PEO Mw 7 Mio g/mol 225.16 187.12 166.83 260.39 245.00polyethylene glycole 6000 60.00 40.00 45.00 65.00 65.10 HPMC 100,000mPas 56.00 56.00 63.00 91.00 98.00 α-tocopherole 0.60 0.40 0.45 0.650.70 SUM 400 400 450 650 700 tablet format oblong oblong oblong H-shapeH-shape 7 × 17 mm 7 × 17 mm 7 × 17 mm 9 × 21 mm 9 × 21 mm

Furthermore, two comparative H-shaped tablets (9×21 mm) containing232.96 mg tapentadol HCl (C-5) and 291.20 mg tapentadol HCl (C-6) weremanufactured without extrusion from conventional excipients notcomprising polyalkylene oxide of high molecular weight.

The breaking strength of the pharmaceutical dosage forms was measured bymeans of a Sotax® HT100 at a constant speed of 120 mm/min. A tablet wasregarded as failing the breaking strength test when during themeasurement the force dropped below the threshold value of 25% of themaximum force that was observed during the measurement, regardless ofwhether the dosage form was fractured into separate pieces or not.

All values are given as mean of 10 measurements (n=10).

The results of the breaking strength measurements are summarized in thetable here below:

direction breaking form type of jaws according to strength C-2 oblongplain FIG. 18B) >500N C-3 oblong plain FIG. 18B) >500N C-4 oblong plainFIG. 18B) >500N C-5 H-shape plain FIG. 18B)   188N C-6 H-shape plainFIG. 18B)   188N I-3 H-shape plain FIG. 18B)   349N I-4 H-shape plainFIG. 18B)   399N I-3 H-shape embossment/indentation FIG. 20A) >500N I-4H-shape embossment/indentation FIG. 20A) >500N I-3 H-shapeembossment/indentation FIG. 20C) >500N I-4 H-shapeembossment/indentation FIG. 20C) >500N

The above breaking strength data demonstrate that the dosage formsaccording to the invention I-3 and I-4 exhibit a breaking strength ofmore than 500 N (B₁) when measured in accordance with FIGS. 20A) and20C) (E₁), even when equipping the tester jaws with embossment andindentation, whereas they exhibit a breaking strength of less than 500 N(B₂) when measured in accordance with FIG. 18B) (E₂).

Nonetheless, the breaking strength (B₂) of the dosage forms according tothe invention I-3 and I-4 when measured in accordance with FIG. 18B)(E₂) is still much higher than that of H-shaped dosage forms that aremanufactured from conventional excipients without extrusion (C-5 andC-6).

Still further, comparative oblong tablets having an increased breakingstrength, such as described in WO2005/016314 or WO2005/016313 (C-2, C-3,and C-4), exhibit a breaking strength of more than 500 N when measuredin accordance with FIG. 18B). Such oblong tablets exhibit a breakingstrength of at least 500 N in each and every direction of extension andthus, are distinguished from the pharmaceutical dosage forms accordingto the invention.

Example 5

Tablets eq200 mg Tapentadol were prepared by extrusion (3.5 kg/h) in twodifferent tablet shapes. The compositions were practically identical(minimal variation in a tocopherol), and had the same weight.

Composition of the tablets eq200 mg Tapentadol (in mg):

tablets 5.1 5.2 Tapentadol HCL 232.96 mg  34.9% 232.96 mg 34.9%  PEO Mw5 Mio 300.38 mg   45% 300.38 mg 45% HPMC 100 000 66.75 mg   10% 66.76 mg10% PEG 66.58 mg 9.975% 66.76 mg 10% α tocopherol 0.83 mg 0.125% 0.66 mg0.1%  tablet weight 667.5 mg 667.5 mg

Percentage drug released for the Tapentadol eq200 mg TRF tested indissolution at 50 rpm paddle speed, USP apparatus II, USP buffer pH 6.8:

5.1 5.2 standard shape H0 shape [%] average average  30 min 10.8 14.9120 min 29.8 34.5 240 min 44.3 51.3 600 min 77.3 84.8

Example 6

Tablets eq250 mg Tapentadol were prepared by extrusion (3.5 kg/h) indifferent tablet shapes. The composition is shown in the next table.

Composition of the eq250 mg Tapentadol TRF tablets (in mg):

Experiment 6 Tapentadol HCL 291.20 mg 34.9%  PEO Mw 5 Mio 375.47 mg 45%HPMC 100 000 83.44 mg 10% PEG 83.44 mg 10% α tocopherol 0.83 mg 0.1% tablet weight 834.38 mg

Percentage drug released for the Tapentadol eq250 mg TRF tested indissolution at 50 rpm paddle speed, USP apparatus II, USP buffer pH 6.8:

standard shape (9 × 21 mm) H1-shape [%] average average  30 min 12.014.1 120 min 29.3 32.2 240 min 46.2 48.2 600 min 78.7 79.3

A first set of comparative tablets was shaped by means of a conventionaloblong plunger, 9×21 mm, and a second set of inventive tablets wasshaped by means of an H-plunger (22.6*8.6 H1, type CPS Batonett,C7084-1, Elisabeth EPMO, France).

1. A pharmaceutical dosage form comprising at least one pharmaceuticallyactive ingredient, and having a shape comprising a longitudinal axis andtwo opposite longitudinal edges, a transversal axis perpendicular to thelongitudinal axis and two opposite transversal edges, a front side, anopposite back side and a circumferential rim between said front and backside, wherein the front side and/or the back side comprise a basis areaand wherein the front side and/or the back side comprise at least onebulge which extends above said basis area, said at least one bulge beingpresent at and/or adjacent to at least a section of one or bothlongitudinal edges and/or at and/or adjacent to at least a section ofone or both transversal edges and/or between both longitudinal edges andboth transversal edges.
 2. The pharmaceutical dosage form according toclaim 1, which is a tablet having an oblong shape.
 3. The pharmaceuticaldosage form according to claim 1, wherein the front side and the backside each comprise at least one bulge at least along a section at and/oradjacent to both longitudinal edges and/or at least along a section atand/or adjacent to both transversal edges.
 4. The pharmaceutical dosageform according to claim 1, wherein said front side and said back sidecomprise an at least essentially continuous bulge at and/or adjacent toat least two third of both opposite longitudinal edges.
 5. Thepharmaceutical dosage form according to claim 1, wherein one or bothlongitudinal edges are essentially straight over at least a major partof their length and/or wherein one or both transversal edges are curvedover a major part of their length.
 6. The pharmaceutical dosage formaccording to claim 1, wherein the front side and/or the back sidecomprise an essentially circumferential bulge at and/or adjacent to thecircumferential edge of the front side and/or the back side of saidpharmaceutical dosage form.
 7. The pharmaceutical dosage form accordingto claim 1, wherein said pharmaceutical dosage form in its oblong formcomprises at and/or adjacent to major portions of both oppositelongitudinal edges of the front side at least one bulge, or wherein saidpharmaceutical dosage form in its oblong form comprises at least onebulge at and/or adjacent to major portions of both opposite longitudinaledges of both the front side and the back side of said pharmaceuticaldosage form, or wherein said pharmaceutical dosage form comprises in itsoblong form a circumferential bulge at and/or adjacent to thecircumferential edge of the front side of said pharmaceutical dosageform, or wherein said pharmaceutical dosage form in its oblong formcomprises a circumferential bulge at and/or adjacent to thecircumferential edge of both the front side and the back side of saidpharmaceutical dosage form.
 8. The pharmaceutical dosage form accordingto claim 7, wherein said pharmaceutical dosage form in its oblong formcomprises at major portions of both opposite longitudinal edges of thefront side at least one bulge, or wherein said pharmaceutical dosageform in its oblong form comprises at least one bulge at major portionsof both opposite longitudinal edges of both the front side and the backside of said pharmaceutical dosage form, or wherein said pharmaceuticaldosage form comprises in its oblong form a circumferential bulge at thecircumferential edge of the front side of said pharmaceutical dosageform, or wherein said pharmaceutical dosage form in its oblong formcomprises a circumferential bulge at the circumferential edge of boththe front side and the back side of said pharmaceutical dosage form. 9.The pharmaceutical dosage form according to claim 7, wherein saidpharmaceutical dosage form in its oblong form comprises adjacent tomajor portions of both opposite longitudinal edges of the front side atleast one bulge, or wherein said pharmaceutical dosage form in itsoblong form comprises at least one bulge adjacent to major portions ofboth opposite longitudinal edges of both the front side and the backside of said pharmaceutical dosage form, or wherein said pharmaceuticaldosage form comprises in its oblong form a circumferential bulgeadjacent to the circumferential edge of the front side of saidpharmaceutical dosage form, or wherein said pharmaceutical dosage formin its oblong form comprises a circumferential bulge adjacent to thecircumferential edge of both the front side and the back side of saidpharmaceutical dosage form.
 10. The pharmaceutical dosage form accordingto claim 7, wherein said pharmaceutical dosage form in its oblong formcomprises a circumferential bulge adjacent to the circumferential edgeof both the front side and the back side of said pharmaceutical dosageform.
 11. The pharmaceutical dosage form according to claim 1, whereinthe front side and/or the back side comprise, in addition to at leastone bulge on the front side and/or the back side, at least oneindentation.
 12. The pharmaceutical dosage form according to claim 11,wherein the front and the back side comprise at least one indentation.13. The pharmaceutical dosage form according to claim 12, wherein theindentation(s) in the front side and the back side are at least once atleast partially off-set.
 14. The pharmaceutical dosage form according toclaim 12, wherein all the indentations of the front side and all theindentations of the back side are at least partially off-set.
 15. Thepharmaceutical dosage form according to claim 12, wherein at least oneindentation of the front side and at least one indentation of the backside are positioned in a congruent manner.
 16. The pharmaceutical dosageform according to claim 15, wherein all indentations of the front sideand all indentations of the back side are positioned in a congruentmanner.
 17. The pharmaceutical dosage form according to claim 11,wherein the indentations have a cylindrical or cube-like or cuboid-likeshape or the shape of a half-sphere.
 18. The pharmaceutical dosage formaccording to claim 1, comprising one or more hydrophilic polymers. 19.The pharmaceutical dosage form according to claim 18, wherein the one ormore hydrophilic polymers are hydroxypropyl methyl cellulose and/orhydroxypropyl cellulose.
 20. The pharmaceutical dosage form according toclaim 18, further comprising pregelatinized starch.
 21. Thepharmaceutical dosage form according to claim 1, wherein thelongitudinal length of the pharmaceutical dosage form does not exceed 30mm.
 22. The pharmaceutical dosage form according to claim 1, having anaverage thickness over the basis areas of the front and the back side ofabout at least 1 mm.
 23. The pharmaceutical dosage form according toclaim 1, wherein the bulge extends perpendicular from the basis area ofthe front side and/or from the basis area of the back side in averagefrom about 0.5 mm to about 2 mm.
 24. The pharmaceutical dosage formaccording to claim 1, having a length in the longitudinal direction inthe range of about 5 mm to about 30 mm, a width in the range of about 5mm to about 15 mm, and a thickness over the basis areas in the range ofabout 1 mm to about 6 mm.
 25. The pharmaceutical dosage form accordingto claim 1, further comprising at least partially a coating. 26.Tamper-resistant pharmaceutical dosage form, which has a retardedrelease profile for pharmaceutical application as an oral dosage form,comprising at least one pharmaceutically active ingredient withpotential for abuse, and having a shape comprising a longitudinal axisand two opposite longitudinal edges, a transversal axis perpendicular tothe longitudinal axis and two opposite transversal edges, a front side,an opposite back side and a circumferential rim between said front andback side, wherein the front side and/or the back side comprise a basisarea and wherein the front side and/or the back side comprise at leastone bulge which extends above said basis area, said at least one bulgebeing present at and/or adjacent to at least a section of one or bothlongitudinal edges and/or at and/or adjacent to at least a section ofone or both transversal edges and/or between both longitudinal edges andboth transversal edges.
 27. The pharmaceutical dosage form according toclaim 26, which is a tablet having an oblong shape.
 28. Thepharmaceutical dosage form according to claim 26, wherein the front sideand the back side each comprise at least one bulge at least along asection at and/or adjacent to both longitudinal edges and/or at leastalong a section at and/or adjacent to both transversal edges.
 29. Thepharmaceutical dosage form according to claim 26, wherein said frontside and said back side comprise an at least essentially continuousbulge at and/or adjacent to at least two third of both oppositelongitudinal edges.
 30. The pharmaceutical dosage form according toclaim 26, wherein one or both longitudinal edges are essentiallystraight over at least a major part of their length and/or wherein oneor both transversal edges are curved over a major part of their length.31. The pharmaceutical dosage form according to claim 26, wherein thefront side and/or the back side comprise an essentially circumferentialbulge at and/or adjacent to the circumferential edge of the front sideand/or the back side of said pharmaceutical dosage form.
 32. Thepharmaceutical dosage form according to claim 26, wherein saidpharmaceutical dosage form in its oblong form comprises at and/oradjacent to major portions of both opposite longitudinal edges of thefront side at least one bulge, or wherein said pharmaceutical dosageform in its oblong form comprises at least one bulge at and/or adjacentto major portions of both opposite longitudinal edges of both the frontside and the back side of said pharmaceutical dosage form, or whereinsaid pharmaceutical dosage form comprises in its oblong form acircumferential bulge at and/or adjacent to the circumferential edge ofthe front side of said pharmaceutical dosage form, or wherein saidpharmaceutical dosage form in its oblong form comprises acircumferential bulge at and/or adjacent to the circumferential edge ofboth the front side and the back side of said pharmaceutical dosageform.
 33. The pharmaceutical dosage form according to claim 32, whereinsaid pharmaceutical dosage form in its oblong form comprises at majorportions of both opposite longitudinal edges of the front side at leastone bulge, or wherein said pharmaceutical dosage form in its oblong formcomprises at least one bulge at major portions of both oppositelongitudinal edges of both the front side and the back side of saidpharmaceutical dosage form, or wherein said pharmaceutical dosage formcomprises in its oblong form a circumferential bulge at thecircumferential edge of the front side of said pharmaceutical dosageform, or wherein said pharmaceutical dosage form in its oblong formcomprises a circumferential bulge at the circumferential edge of boththe front side and the back side of said pharmaceutical dosage form. 34.The pharmaceutical dosage form according to claim 32, wherein saidpharmaceutical dosage form in its oblong form comprises adjacent tomajor portions of both opposite longitudinal edges of the front side atleast one bulge, or wherein said pharmaceutical dosage form in itsoblong form comprises at least one bulge adjacent to major portions ofboth opposite longitudinal edges of both the front side and the backside of said pharmaceutical dosage form, or wherein said pharmaceuticaldosage form comprises in its oblong form a circumferential bulgeadjacent to the circumferential edge of the front side of saidpharmaceutical dosage form, or wherein said pharmaceutical dosage formin its oblong form comprises a circumferential bulge adjacent to thecircumferential edge of both the front side and the back side of saidpharmaceutical dosage form.
 35. The pharmaceutical dosage form accordingto claim 32, wherein said pharmaceutical dosage form in its oblong formcomprises a circumferential bulge adjacent to the circumferential edgeof both the front side and the back side of said pharmaceutical dosageform.
 36. The pharmaceutical dosage form according to claim 26, whereinthe front side and/or the back side comprise, in addition to at leastone bulge on the front side and/or the back side, at least oneindentation.
 37. The pharmaceutical dosage form according to claim 36,wherein the front and the back side comprise at least one indentation.38. The pharmaceutical dosage form according to claim 37, wherein theindentation(s) in the front side and the back side are at least once atleast partially off-set.
 39. The pharmaceutical dosage form according toclaim 37, wherein all the indentations of the front side and all theindentations of the back side are at least partially off-set.
 40. Thepharmaceutical dosage form according to claim 36, wherein at least oneindentation of the front side and at least one indentation of the backside are positioned in a congruent manner.
 41. The pharmaceutical dosageform according to claim 40, wherein all indentations of the front sideand all indentations of the back side are positioned in a congruentmanner.
 42. The pharmaceutical dosage form according to claim 36,wherein the indentations have a cylindrical or cube-like or cuboid-likeshape or the shape of a half-sphere.
 43. The pharmaceutical dosage formaccording to claim 26, comprising a polyalkylene oxide.
 44. Thepharmaceutical dosage form according to claim 26, comprising at leastone cellulose ether derivative.
 45. The pharmaceutical dosage formaccording to claim 44, wherein the cellulose ether derivative is HPMC.46. The pharmaceutical dosage form according to claim 43, wherein thepolyalkylene oxide is polyethylene oxide.
 47. The pharmaceutical dosageform according to claim 46, wherein the polyethylene oxide has amolecular weight in the range of about 2,000,000 to about 7,000,000. 48.The pharmaceutical dosage form according to claim 26, wherein thepharmaceutical dosage form further comprises a polyalkylene glycol. 49.The pharmaceutical dosage form according to claim 48, wherein thepolyalkylene glycol is polyethylene glycol.
 50. The pharmaceuticaldosage form according to claim 26, wherein the pharmaceutically activeingredient with potential for abuse is a pain-killing drug.
 51. Thepharmaceutical dosage form according to claim 50, wherein thepharmaceutically active ingredient is tapentadol.
 52. The pharmaceuticaldosage form according to claim 26, comprising at least onepharmaceutically active ingredient with potential for abuse; at leastone poly(alkylene oxide); at least one cellulose ether derivative; andat least one polyalkylene glycol; and optionally an additive.
 53. Thepharmaceutical dosage form according to claim 52, wherein the activeingredient with potential for abuse is present in an amount of at least5 weight percent; poly(alkylene oxide) is present in an amount of atleast 15 weight percent; cellulose ether derivative is present in anamount of at least 5 weight percent; and polyalkylene glycol is presentin an amount of at least 5 weight percent.
 54. The pharmaceutical dosageform according to claim 26, wherein the longitudinal length of thepharmaceutical dosage form does not exceed 30 mm.
 55. The pharmaceuticaldosage form according to claim 26, having an average thickness over thebasis areas of the front and the back side of about at least 1 mm. 56.The pharmaceutical dosage form according to claim 26, wherein the bulgeextends perpendicular from the basis area of the front side and/or fromthe basis area of the back side in average from about 0.5 mm to about 2mm.
 57. The pharmaceutical dosage form according to claim 26, having alength in the longitudinal direction in the range of about 5 mm to about30 mm, a width in the range of about 5 mm to about 15 mm, and athickness over the basis areas in the range of about 1 mm to about 6 mm.58. The pharmaceutical dosage form according to claim 26, wherein saidpharmaceutical dosage form is a monolith.
 59. The pharmaceutical dosageform according to claim 26, which has been prepared via compressionusing a die and a punch from a monolithic mass obtained by meltextrusion.
 60. The pharmaceutical dosage form according to claim 58,wherein said pharmaceutical dosage form has been obtained by compressinga melt extruded monolithic mass which exhibits ambient temperature. 61.The pharmaceutical dosage form according to claim 58, wherein theextruded monolithic mass has been cut prior to compression.
 62. Thepharmaceutical dosage form according to claim 58, wherein melt extrusionhas been conducted with a twin-screw extruder.
 63. The pharmaceuticaldosage form according to claim 26, further comprising at least partiallya coating.
 64. A method of treating pain in a patient in need of suchtreatment, said method comprising administering to said patient aneffective amount therefor of a pharmaceutical dosage form according toclaim 1, wherein the pharmaceutically active ingredient, thepharmaceutically active ingredient with potential for abuse and thepharmacologically active compound (A) are each selected from the groupconsisting of analgesics.